| HOME | HELP | FEEDBACK | SUBSCRIPTIONS | ARCHIVE | SEARCH | TABLE OF CONTENTS |
Genetics, Vol. 170, 543-553, June 2005, Copyright © 2005
doi:10.1534/genetics.104.038570
| ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
* Department of Biochemistry, University of Cambridge, Cambridge CB2 1GA, United Kingdom
The Gurdon Cancer Research UK Institute, University of Cambridge, Cambridge CB2 1QN, United Kingdom
1 Corresponding author: Department of Biochemistry, Cambridge University, 80 Tennis Court Rd., Cambridge CB2 1GA, United Kingdom.
E-mail: jad32{at}mole.bio.cam.ac.uk
 |
ABSTRACT |
|---|
 TOP ABSTRACT MATERIALS AND METHODSRESULTSDISCUSSIONACKNOWLEDGEMENTSLITERATURE CITED |
|---|
At its most basic level, chromatin is composed of DNA wrapped around an octamer of histone proteins, made up of an (H3-H4)2 tetramer and two H2A-H2B dimers, to form the nucleosome. Beyond this level of organization, chromatin can form more compact, higher-order structures, and this is mediated in part by the presence of linker histones. The compaction of DNA in this manner has been shown to be generally inhibitory to its manipulation and accessibility. By modulating chromatin structure, cells can achieve precise regulation of DNA-dependent functions such as transcription. Chromatin structure is modulated by two primary mechanisms: ATP-dependent chromatin remodeling and covalent modification of histone tails. Recent evidence suggests that both of these mechanisms are utilized by cells to facilitate DNA DSB repair. For example, yeast strains with mutations in either Ino80C or Swr-C ATP-dependent chromatin-remodeling complexes are sensitive to DNA-damaging agents (SHEN et al. 2000; MIZUGUCHI et al. 2004). Additionally, covalent modification of the histone H4 N-terminal tail by the NuA4 histone acetyl transferase (HAT) complex has been implicated in DNA DSB repair (BIRD et al. 2002). Consistent with this, expression of an enzymatically inactive subunit of a mammalian HAT complex that is homologous to the catalytic subunit of NuA4 results in slower double-strand-break repair (IKURA et al. 2000). Additionally, histone deacetylase activities have recently been implicated in DNA DSB repair (FERNANDEZ-CAPETILLO and NUSSENZWEIG 2004), raising the possibility that a complex series of chromatin-mediated events takes place after DNA damage. It is possible that these activities indirectly affect survival under these conditions by compromising the ability of cells to appropriately regulate transcription of genes necessary for normal DNA damage responses. Recently, however, subunits of the NuA4, Ino80-C, and Swr1C complexes have been found to be present at the site of DNA DSBs by chromatin immunoprecipitation (ChIP) assays (BIRD et al. 2002; DOWNS et al. 2004; MORRISON et al. 2004; VAN ATTIKUM et al. 2004), suggesting that there is a direct role for one or more of these complexes in DNA repair.
One covalent chromatin modification that has been found to be directly involved in DNA DSB responses is the phosphorylation of the mammalian histone variant H2A-X on the carboxyl-terminal tail at position S139 (ROGAKOU et al. 1998). This has been shown to occur in proximity to DNA lesions (ROGAKOU et al. 1999) and is mediated by the PIKK family members ATM, ATR, and DNA-PK (PAULL et al. 2000; BURMA et al. 2001; WARD and CHEN 2001). In yeast, this serine residue exists on the main H2A species (S129) and is phosphorylated in response to DNA damage by the PIKK family members Mec1 and Tel1 (DOWNS et al. 2000; REDON et al. 2003). Consistent with data generated in higher eukaryotes, we and others recently found that S129 is phosphorylated in the vicinity of DNA DSBs by ChIP analysis (DOWNS et al. 2004; MORRISON et al. 2004; SHROFF et al. 2004; VAN ATTIKUM et al. 2004), suggesting that this covalent modification directly facilitates repair at the site of the DNA lesion. In addition to residues that are targets for covalent modifications or chromatin-remodeling activities, residues that contribute directly to chromatin structure are important for the ability of cells to appropriately access and manipulate DNA. For example, residues in histone H2B that are unlikely to be modified have been shown to be important for mediating DNA repair by the postreplicative pathway (MARTINI et al. 2002).
To determine whether there was a contribution to DNA damage responses being provided by residues in the H2A C-terminal tail in addition to that of S129, we examined the histone H2A C-terminal tail by systematic site-directed mutagenesis. We find that one residue, S122, is important for survival in the presence of DNA damage. Furthermore, we demonstrate that H2A S122 is not required for the Mec1-dependent DNA damage signal transduction cascade, suggesting a more direct role in the repair event itself. We also find that H2A S122A mutant yeast are drastically impaired in their ability to sporulate, pointing to a potential role in homologous recombination. In support of this hypothesis, continual expression of the homothallic (HO) endonuclease results in decreased survival in the H2A S122A mutant yeast strain. Finally, we show that this residue functions independently from H2A S129, suggesting the presence of a complex DNA DSB repair histone code.
|
MATERIALS AND METHODS |
|---|
|
TOPABSTRACTMATERIALS AND METHODSRESULTSDISCUSSIONACKNOWLEDGEMENTSLITERATURE CITED |
|---|
) with FY406 and sporulating. The resulting haploid strains were selected for loss of pAB6 by growth on 5-FOA-containing media and were subsequently analyzed for the presence of hta1-S122A by PCR and for hta2-htb2::TRP1 disruption by phenotypic analysis.
|
|
To measure sensitivity to the expression of the EcoRI endonuclease, equal numbers of midlog yeast cells containing either the endonuclease gene under the control of the GAL1-10 promoter or an empty vector were grown in media containing 2% galactose as the sole carbon source. Surviving colonies were then counted after 4 days and are presented as the percentage of survival of the strains containing the endonuclease relative to the survival of the strains containing the empty vector. To measure sensitivity to the expression of the HO endonuclease, equal numbers of midlog yeast cells containing the HO endonuclease under the control of the GAL1-10 promoter were plated onto media containing either glucose or galactose as the sole carbon source, and surviving colonies were counted after 4 days. Survival is presented as the percentage of colonies on galactose-containing media relative to colonies on glucose-containing media. These assay were performed using strain JDY94 with or without complementation with wild-type HTA1.
Western blot analysis:
For preparation of whole-cell extracts for Western blot analysis, midlog cultures were either treated with 0.1% MMS or left untreated for 1 hr at 30° and then lysed using glass bead disruption into 20% trichloracetic acid. Lysates were electrophoresed on 18% (for H2A analysis) or 7.5% (for Rad53 analysis) SDS polyacrylamide gels and transferred to nitrocellulose membranes. Membranes were blocked using 5% (w/v) milk (Marvel) in Tris-buffered-saline containing 0.1% (v/v) Tween 20 (TBS-T) and then incubated with the indicated polyclonal primary antibody for 2 hr (for H2A and Tip49a analysis) or overnight (for Rad53 analysis) diluted in TBS-T. To detect H2A-S129 phosphorylation, an affinity-purified antibody specific for this modification (DOWNS et al. 2000) was used at a 1:1000 dilution. To detect H2A protein levels, antiserum that recognizes H2A regardless of S129 phosphorylation status (DOWNS et al. 2000) was used at a 1:4000 dilution in 5% milk in TBS-T. To detect Rad53, an antibody that recognizes unphosphorylated and hyperphosphorylated forms of the protein (gift of N. Lowndes) was used at 1:10,000 dilution. To detect Tip49a, an antibody raised against recombinant Tip49a was used at 1:1000 in TBS-T (gift of J. Cote). Signal was detected using horseradish-peroxidase-coupled anti-rabbit secondary antibody (Pierce, Rockford, IL) and enhanced chemiluminescence (Pierce).
Micrococcal nuclease digestion:
Spheroplasts were prepared according to a protocol developed by KENT and MELLOR (1995). Briefly, 100-ml midlog cultures were harvested and normalized by measuring the OD600nm. Cell pellets were washed once in water, resuspended in 950 µl of freshly made YLE buffer [10 mg/ml zymolyase, 20,000 units/g (ICN), 1 M sorbitol, and 5 mM ß-mercaptoethanol) and then incubated for 15 min at room temperature. The resulting spheroplasts were collected by centrifugation, gently washed twice in 950 µl of 1 M sorbitol, and resuspended in 1.2 ml of spheroplast digestion buffer (1 M sorbitol, 50 mM NaCl, 10 mM Tris-HCl pH 7.5, 5 mM MgCl2, 1 mM ß-mercaptoethanol, 0.5 mM spermidine, and 0.075% nonidet P40). To this, 15 µl of 2.86 units/ml micrococcal nuclease (MNase; Sigma, St. Louis) was added and the reaction was incubated at 37°. At the indicated time points, 200-µl aliquots were removed and added to fresh microfuge tubes containing 20 µl of stop solution (5% SDS, 250 mM EDTA). The DNA was then purified by phenol/chloroform extraction and ethanol precipitation, analyzed on a 1% agar gel, and visualized with ethidium bromide.
Sporulation analysis:
Strains were grown overnight in YPAD, diluted 1:50 into YPA, and grown another 24 hr at 30°. The cultures were then washed two times in water and resuspended in sporulation media. After 5 days in sporulation media, cells were fixed in formaldehyde and examined microscopically for the presence of spores. Minimally, 300 cells were counted for each culture, and three independent sporulation cultures were analyzed per strain.
DNA damage checkpoint analysis:
Yeast cultures were grown to midlog phase and treated with 15 µg/ml nocodazole (Sigma) for 2.5 hr at 30°. One hour prior to release from nocodazole, MMS was added to one set of cultures to a final concentration of 0.10%. The cultures were then washed once and resuspended in fresh medium. Aliquots were removed at the indicated times, fixed with 5% formaldehyde, and sonicated. Samples were analyzed microscopically for the presence of large-budded cells (defined as cells with buds >70% the size of the mother cell).
|
RESULTS |
|---|
|
TOPABSTRACTMATERIALS AND METHODSRESULTSDISCUSSIONACKNOWLEDGEMENTSLITERATURE CITED |
|---|
|
Interestingly, it has already been shown that H2A S122 is phosphorylated in vivo (WYATT et al. 2003), although the timing and location of phosphorylation as well as the biological role of this event are as yet unknown. To investigate the possibility that phosphorylation of H2A S122 is important for survival in the presence of DNA damage, we created a strain in which S122 was replaced with a glutamic acid residue, which can, in some cases, mimic phosphorylation. This strain, however, appeared to be as sensitive to DNA damage as the hta1-S122A strain (Figure 2A), and exhibited the same slow growth as the hta1-S122A strain (Figure 2B). We next raised an antiserum against a peptide containing a phosphoserine residue corresponding to S122. While this antiserum was able to recognize the phospho-peptide, we were unable to detect phosphorylation of H2A S122 by Western blot analysis of both whole-cell extracts and histone preparations prepared from wild-type yeast under a variety of conditions, including treatment with MMS (data not shown). Therefore, while it is clear that H2A S122 is important for survival in the presence of MMS, we are unable to determine whether phosphorylation of this residue is important for this function.
|
40 min longer than untreated cells (Figure 3B). This was in good agreement with the MMS-induced arrest seen in the wild-type strain (Figure 3B), indicating that the G2/M DNA damage checkpoint is intact in the hta1-S122A mutant strain.
|
Survival in the presence of DNA double-strand breaks is impaired in the hta1-S122A mutant strain:
Next, we tested our panel of histone H2A mutants for their ability to survive in the presence of a range of DNA-damaging agents that cause different DNA lesions. With the exception of hta1-K121A, which showed a weak sensitivity to camptothecin (Figure 4B), strains with mutations in other C-terminal tail residues of H2A did not show any significant phenotypes relative to the wild-type control in the presence of the drugs tested (Figure 4, A–F), suggesting that these residues are not individually important in mediating DNA damage responses in vivo. These results are in contrast to a previous report demonstrating that a strain with a T126A mutation in H2A is sensitive to bleomycin (WYATT et al. 2003). There are numerous possible explanations for this discrepancy, including differences in the drugs tested, the assay conditions, and the yeast strains used in the two studies.
|
As previously mentioned, DNA DSB repair is performed by two major pathways in eukaryotes: HR and NHEJ. The repair of DNA DSBs by HR is an integral part of meiosis and strains lacking DNA damage signaling and repair genes are often defective in their ability to sporulate. We therefore analyzed the ability of the hta1-S122A strain to sporulate. Interestingly, after 5 days in sporulation media, the hta1-S122A mutant strain had 55-fold fewer spores than the wild-type strain (Figure 5A; 0.426 vs. 23.63%), demonstrating a defect in the ability to sporulate. It has previously been shown that NHEJ is downregulated in diploid cells when HR is the preferred pathway for DNA DSB repair (VALENCIA et al. 2001). We therefore examined the role of S122 in diploid strains in parallel with our haploid strains to see whether a difference in survival in the presence of DNA damage was apparent. In response to the presence of MMS, the diploid hta1-S122A mutant strain showed the same phenotype as the haploid hta1-S122A mutant strain (Figure 5B), indicating that the role of H2A S122 in mediating survival is not exclusive to haploid yeast. Taken together, these data are suggestive of a role in mediating HR responses. To further investigate this possibility, we examined the ability of hta1-S122A mutant yeast to survive in the presence of continual HO endonuclease expression. Survival under these conditions is severely compromised in strains lacking HR activity. In doing so, we found a modest, but reproducible decrease in survival when compared with the wild-type strain (Figure 5C). We additionally examined the ability of cells to survive in the presence of EcoRI expression, which severely compromises the ability of NHEJ-defective yeast to survive (LEWIS et al. 1998). Interestingly, we found that survival in this assay was also reproducibly reduced in the hta1-S122A mutant yeast (Figure 5D). While this result is suggestive of a role for H2A S122 in NHEJ-mediated DNA repair responses, we note that the phenotype detected in the hta1-S122A mutant yeast strain is significantly less severe than that detected in strains lacking NHEJ components. Moreover, strains lacking genes required for HR are mildly sensitive to the overexpression of EcoRI (LEWIS et al. 1998), making it difficult to definitively place H2A S122 on either DNA DSB repair pathways. Nevertheless, these assays clearly demonstrate that survival in the presence of DNA double-strand breaks is defective in the hta1-S122A mutant strain.
|
While the DNA damage sensitivity profiles of the hta1-S122A, hta1-S129A, and hta1-S122A/S129A mutant strains imply that the two residues work independently to facilitate DNA repair, there are other viable interpretations, particularly since these residues are in such close proximity on the same molecule. For instance, if both residues are important for binding by a common downstream factor and each single mutation reduces, but does not abrogate, binding, then the double-mutant strain in which binding is further impaired would have a more severe phenotype than either single-mutant strain. To discriminate between these possibilities, we performed a complementation experiment in which we supplied the yeast with two H2A-expressing plasmids. As expected, a strain containing two hta1-S122A mutant constructs was significantly more sensitive to MMS than a strain containing two wild-type constructs (Figure 6E; compare the top row to the the fourth row). This is also the case for a strain containing two hta1-S129A mutant constructs (Figure 6E; compare the top and bottom rows). Importantly, strains containing one wild-type H2A construct and one mutant H2A construct are no more sensitive to MMS than the wild-type strain is, demonstrating that the hta1-S122A and hta1-S129A mutations are both recessive (Figure 6E; compare the top row to the second and third rows). Importantly, however, if cells contain one hta1-S122A mutant construct and one hta1-S129A mutant construct, the strain is indistinguishable from the wild-type strain in the presence of DNA damage (Figure 6E; compare the top row to the fifth row), demonstrating that both mutant phenotypes can be complemented by the presence of the other mutant H2A. These data indicate that the two residues provide independent functions and that if both serines are present, regardless of whether they are on the same histone molecule, this is sufficient for the cell to respond appropriately and to survive in the presence of DNA damage.
As previously mentioned, it has been demonstrated that H2A S122 and S129 are phosphorylated (DOWNS et al. 2000; WYATT et al. 2003). Interestingly, H2A T126 was also found to be phosphorylated, and in an hta1-S122P mutant strain, the amount of phosphorylation at other sites was increased (WYATT et al. 2003). Therefore, one possible mechanism by which loss of H2A S122 affects DNA damage responses is via increased H2A T126 phosphorylation, which indirectly inhibits normal H2A S129 responses. The different profiles of hta1-S122A and hta1-S129A phenotypes and DNA damage sensitivities make this an unlikely explanation. Nevertheless, to test this hypothesis, we made an hta1-S122A/T126A double-mutant strain to remove the possibility that T126 was phosphorylated inappropriately. If H2A S122 contributes to DNA damage responses only by preventing inappropriate H2A T126 phosphorylation, then there should be no DNA damage sensitivity when both residues are changed to alanine residues. In contrast to this hypothesis, we find that the hta1-S122A/T126A double mutant is still sensitive to the presence of DNA damage (Figure 6F). Additionally, an hta1-T126A/S129A mutant strain is no more sensitive than an hta1-S129A mutant strain, and an hta1-S122A/T126A/S129A mutant strain is no more sensitive to DNA damage than an hta1-S122A/S129A mutant strain (Figure 6F), suggesting that H2A T126 plays no significant role in DNA damage responses in these assays. Importantly, these data indicate that H2A S122 provides a function in mediating DNA damage responses that is independent of H2A T126 and further supports the conclusion that the function is also independent of H2A S129.
|
DISCUSSION |
|---|
|
TOPABSTRACTMATERIALS AND METHODSRESULTSDISCUSSIONACKNOWLEDGEMENTSLITERATURE CITED |
|---|
Regardless of whether H2A S122 is phosphorylated, these studies demonstrate that it is important in yeast for DNA damage responses and show that this residue provides a function independent from the known DNA-damage-responsive residue H2A S129. The role of histone H2A S129 in response to DNA damage has been shown to be conserved in a number of eukaryotes (ROGAKOU et al. 1999). As previously mentioned, the motif surrounding S129 exists on the major H2A species in some lower eukaryotes, such as Saccharomyces cerevisiae, but is found on histone variants in higher eukaryotes, such as H2AX in humans, and not in the major H2A species. We investigated the conservation of sequences homologous to S. cerevisiae H2A S122 and found that, while the sequence downstream of S122 is not well conserved, the sequence immediately upstream of S122 is highly conserved and is present in the eukaryotic organisms that we have examined thus far (Figure 7). The conserved upstream sequence is present in the major histone H2A encoding genes as well as in some H2AX and H2AF/Z variants. Moreover, S122 itself is reasonably highly conserved, and the analogous residue is a serine or threonine, again pointing to the strong possibility that phosphorylation will play a role in its cellular function. The degree of conservation of this region of histone H2A is suggestive of a conserved function, and it will be of great interest to determine whether the analogous residue in other eukaryotes is also important in DNA damage responses.
|
Additionally, S122 might be necessary to create a chromatin structure that is compatible with the manipulation required for DNA repair. While the gross chromatin structure in an hta1-S122A-containing strain is indistinguishable from wild-type chromatin, it is possible that subtle differences in chromatin structure that would be undetectable in our assays could have profound effects on the ability of DNA in the vicinity of lesions to be appropriately manipulated. These possibilities are currently being investigated. From the data presented here, it is clear that multiple histone residues are important for mediating DNA repair and, with the emerging studies of chromatin-modulating activities in DNA repair, suggest the existence of a complex DNA-damage-dependent histone code.
|
ACKNOWLEDGEMENTS |
|---|
|
TOPABSTRACTMATERIALS AND METHODSRESULTSDISCUSSIONACKNOWLEDGEMENTSLITERATURE CITED |
|---|
|
LITERATURE CITED |
|---|
|
TOPABSTRACTMATERIALS AND METHODSRESULTSDISCUSSIONACKNOWLEDGEMENTSLITERATURE CITED |
|---|
AIHARA, H., T. NAKAGAWA, K. YASUI, T. OHTA, S. HIROSE et al., 2004 Nucleosomal histone kinase-1 phosphorylates H2A Thr119 during mitosis in the early Drosophila embryo. Genes Dev. 18: 877–888.
BIRD, A. W., D. Y. YU, M. G. PRAY-GRANT, Q. QIU, K. E. HARMON et al., 2002 Acetylation of histone H4 by Esa1 is required for DNA double-strand break repair. Nature 419: 411–415.[CrossRef][Medline]
BURMA, S., B. P. CHEN, M. MURPHY, A. KURIMASA and D. J. CHEN, 2001 ATM phosphorylates histone H2AX in response to DNA double-strand breaks. J. Biol. Chem. 276: 42462–42467.
COSTIGAN, C., D. KOLODRUBETZ and M. SNYDER, 1994 NHP6A and NHP6B, which encode HMG1-like proteins, are candidates for downstream components of the yeast SLT2 mitogen-activated protein kinase pathway. Mol. Cell. Biol. 14: 2391–2403.
DOWNS, J. A., N. F. LOWNDES and S. P. JACKSON, 2000 A role for Saccharomyces cerevisiae histone H2A in DNA repair. Nature 408: 1001–1004.[CrossRef][Medline]
DOWNS, J. A., S. ALLARD, O. JOBIN-ROBITAILLE, A. JAVAHERI, A. AUGER et al., 2004 Binding of chromatin-modifying activities to phosphorylated histone H2A at DNA damage sites. Mol. Cell 17: 979–990.
FERNANDEZ-CAPETILLO, O., and A. NUSSENZWEIG, 2004 Linking histone deacetylation with the repair of DNA breaks. Proc. Natl. Acad. Sci. USA 101: 1427–1428.
HIRSCHHORN, J. N., A. L. BORTVIN, S. L. RICUPERO-HOVASSE and F. WINSTON, 1995 A new class of histone H2A mutations in Saccharomyces cerevisiae causes specific transcriptional defects in vivo. Mol. Cell. Biol. 15: 1999–2009.[Abstract]
IKURA, T., V. V. OGRYZKO, M. GRIGORIEV, R. GROISMAN, J. WANG et al., 2000 Involvement of the TIP60 histone acetylase complex in DNA repair and apoptosis. Cell 102: 463–473.[CrossRef][Medline]
KENT, N. A., and J. MELLOR, 1995 Chromatin structure snap-shots: rapid nuclease digestion of chromatin in yeast. Nucleic Acids Res. 23: 3786–3787.
LEWIS, L. K., J. M. KIRCHNER and M. A. RESNICK, 1998 Requirement for end-joining and checkpoint functions, but not RAD52-mediated recombination, after EcoRI endonuclease cleavage of Saccharomyces cerevisiae DNA. Mol. Cell. Biol. 18: 1891–1902.
LIEBER, M. R., Y. MA, U. PANNICKE and K. SCHWARZ, 2003 Mechanism and regulation of human non-homologous DNA end-joining. Nat. Rev. Mol. Cell Biol. 4: 712–720.[CrossRef][Medline]
MARTINI, E. M. D., S. KEENEY and M. A. OSLEY, 2002 A role for histone H2B during repair of UV-induced DNA damage in Saccharomyces cerevisiae. Genetics 160: 1375–1387.
MIZUGUCHI, G., X. SHEN, J. LANDRY, W.-H. WU, S. SEN et al., 2004 ATP-driven exchange of histone H2AZ variant catalyzed by SWR1 chromatin remodeling complex. Science 303: 343–348.
MORRISON, A. J., J. HIGHLAND, N. J. KROGAN, A. ARBEL-EDEN, J. F. GREENBLATT et al., 2004 INO80 and g-H2AX interaction links ATP-dependent chromatin remodeling to DNA damage repair. Cell 119: 767–775.[CrossRef][Medline]
PAULL, T. T., E. P. ROGAKOU, V. YAMAZAKI, C. U. KIRCHGESSNER, M. GELLERT et al., 2000 A critical role for histone H2AX in recruitment of repair factors to nuclear foci after DNA damage. Curr. Biol. 10: 886–895.[CrossRef][Medline]
REDON, C., D. R. PILCH, E. ROGAKOU, A. H. ORR, N. F. LOWNDES et al., 2003 Yeast histone 2A serine 129 is essential for the efficient repair of checkpoint-blind DNA damage. EMBO Rep. 4: 1–7.[CrossRef]
ROGAKOU, E. P., D. R. PILCH, A. H. ORR, V. S. IVANOVA and W. M. BONNER, 1998 DNA double-stranded breaks induce histone H2AX phosphorylation on serine 139. J. Biol. Chem. 273: 5858–5868.
ROGAKOU, E. P., C. BOON, C. REDON and W. M. BONNER, 1999 Megabase chromatin domains involved in DNA double-strand breaks in vivo. J. Cell Biol. 146: 905–915.
ROUSE, J., and S. P. JACKSON, 2002 Interfaces between the detection, signaling, and repair of DNA damage. Science 297: 547–551.
SANCHEZ, Y., B. A. DESANY, W. J. JONES, Q. LIU, B. WANG et al., 1996 Regulation of RAD53 by the ATM-like kinases MEC1 and TEL1 in yeast cell cycle checkpoint pathways. Science 271: 357–360.[Abstract]
SHEN, X., G. MIZUGUCHI, A. HAMICH and C. WU, 2000 A chromatin remodeling complex involved in transcription and DNA processing. Nature 406: 541–544.[CrossRef][Medline]
SHROFF, R., A. ARBEL-EDEN, D. PILCH, G. IRA, W. M. BONNER et al., 2004 Distribution and dynamics of chromatin modification induced by a defined DNA double-strand break. Curr. Biol. 14: 1703–1711.[CrossRef][Medline]
VALENCIA, M., M. BENTELE, M. B. VAZE, G. HERRMANN, E. KRAUS et al., 2001 NEJ1 controls non-homologous end joining in Saccharomyces cerevisiae. Nature 416: 666–669.[CrossRef]
VAN ATTIKUM, H., O. FRITSCH, B. HOHN and S. M. GASSER, 2004 Recruitment of the INO80 complex by H2A phosphorylation links ATP-dependent chromatin remodeling with DNA double-strand break repair. Cell 119: 777–788.[CrossRef][Medline]
WARD, I. M., and J. CHEN, 2001 Histone H2AX is phosphorylated in an ATR-dependent manner in response to replicational stress. J. Biol. Chem. 276: 47759–47762.
WEINERT, T., 1998 DNA damage and checkpoint pathways: molecular anatomy and interactions with repair. Cell 94: 555–558.[CrossRef][Medline]
WEST, S. C., 2003 Molecular views of recombination proteins and their control. Nat. Rev. Mol. Cell Biol. 4: 1–11.
WHITE, C. L., R. K. SUTO and K. LUGER, 2001 Structure of the yeast nucleosome core particle reveals fundamental changes in internucleosome interactions. EMBO J. 20: 5207–5218.[CrossRef][Medline]
WYATT, H. R., H. LIAW, G. R. GREEN and A. J. LUSTIG, 2003 Multiple roles for Saccharomyces cerevisiae histone H2A in telomere position effect, Spt phenotypes and double-strand-break repair. Genetics 164: 47–64.
YOSHIDA, K., H.-G. WANG, Y. MIKI and D. KUFE, 2003 Protein kinase C
is responsible for constitutive and DNA damage-induced phosphorylation of Rad9. EMBO J. 22: 1431–1441.[CrossRef][Medline]
This article has been cited by other articles:
 |
|
 |
|
  D. Biswas, S. Takahata, and D. J. Stillman Different Genetic Functions for the Rpd3(L) and Rpd3(S) Complexes Suggest Competition between NuA4 and Rpd3(S) Mol. Cell. Biol., July 15, 2008; 28(14): 4445 - 4458. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 H. Ogiwara, A. Ui, S. Kawashima, K. Kugou, F. Onoda, H. Iwahashi, M. Harata, K. Ohta, T. Enomoto, and M. Seki Actin-related protein Arp4 functions in kinetochore assembly Nucleic Acids Res., May 14, 2007; 35(9): 3109 - 3117. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 J. D. Moore, O. Yazgan, Y. Ataian, and J. E. Krebs Diverse Roles for Histone H2A Modifications in DNA Damage Response Pathways in Yeast Genetics, May 1, 2007; 176(1): 15 - 25. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 K. Matsubara, N. Sano, T. Umehara, and M. Horikoshi Global analysis of functional surfaces of core histones with comprehensive point mutants. Genes Cells, January 1, 2007; 12(1): 13 - 33. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
C. Redon, D. R. Pilch, and W. M. Bonner Genetic Analysis of Saccharomyces cerevisiae H2A Serine 129 Mutant Suggests a Functional Relationship Between H2A and the Sister-Chromatid Cohesion Partners Csm3-Tof1 for the Repair of Topoisomerase I-Induced DNA Damage Genetics, January 1, 2006; 172(1): 67 - 76. [Abstract] [Full Text] [PDF]
|
|
| ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| HOME | HELP | FEEDBACK | SUBSCRIPTIONS | ARCHIVE | SEARCH | TABLE OF CONTENTS |
