Genetics, Vol. 173, 1181-1185, July 2006, Copyright © 2006

Chromosome Breakage and Repair

James E. Haber1

Rosenstiel Center and Department of Biology, Brandeis University, Waltham, Massachusetts 02454-9110

1 Address for correspondence: 415 South St., Rosenstiel Center, Department of Biology, Brandeis University, Waltham, MA 02454-9110.
E-mail: haber{at}brandeis.edu

FROM time to time one of my colleagues working at a medical school commiserates with me because I spend ~40 hr a year lecturing to undergraduates. I always reply that teaching has compelled me to learn a lot of material that I would not have known about had I taught only my specialized subject. These forays into the "beyond" were instrumental in moving my research in new directions. Three articles that I published in GENETICS in the early 1980s (MCCUSKER and HABER 1981; HABER and THORBURN 1984; HABER et al. 1984) were the result of learning about, in order to teach, classic genetic experiments in Drosophila and maize.

When I arrived at Brandeis I was assigned to teach genetics, a subject I had never studied as either an undergraduate or a graduate student2. I was fortunate to team up in teaching with Jeff Hall, a master geneticist, who taught me much of the lore of Drosophila and maize, to add to the yeast genetics that my lab and I were slowly learning3. I was particularly interested in Barbara McClintock's study of the "Activator (Ac)/Dissociator (Ds)" transposable elements whose excisions led to cycles of breakage–fusion–bridge (BFB) of broken chromosome ends that generated chromosomal truncations. Her studies resonated strongly with the behavior of apparently broken chromosomes that we were studying in budding yeast as a consequence of mating-type gene switching.

The study of yeast mating-type (MAT) gene switching has provided gainful employment for many scientists interested in cell-type regulation, gene silencing, chromosome architecture, and DNA repair. Haploid cells express either the MATa or the MAT{alpha} allele and mate with cells of the opposite type, but cells expressing both MATa and MAT{alpha} are nonmating. But most unusual was that homothallic MATa cells could switch to MAT{alpha}, or vice versa, as often as every cell division. TAKANO and OSHIMA (1970; OSHIMA and TAKANO 1971) showed that switching depended on two distant loci that they viewed as "controlling elements," similar to those defined by McClintock in maize. HICKS et al. (1977) made the insightful suggestion that these two loci were in fact unexpressed copies of mating-type information (now called HML{alpha} and HMRa) that could be transposed to replace the original MAT allele. Extending the mutational analysis of MACKAY and MANNEY (1974) and the sometimes-published work of the inventive Don Hawthorne (HAWTHORNE 1963; see also HERSKOWITZ 1988), STRATHERN et al. (1981) proposed that MAT{alpha} encoded both a repressor of a-specific genes (MAT{alpha}2) and a positive regulator of {alpha}-specific genes (MAT{alpha}1). Thus a mat{alpha}1 mat{alpha}2 mutant proved to be a-like.

The transposition/replacement of MAT alleles occurs very frequently in homothallic cells, expressing the HO gene encoding a site-specific endonuclease, but is very rare in heterothallic strains where HO is inactive. One way we tried to study these rare events was by mating two heterothallic MAT{alpha} strains together, on the assumption that if one of them switched to MATa, it would readily conjugate with a MAT{alpha} cell, as first shown by HAWTHORNE (1963). We took up this approach (MCCUSKER and HABER 1981) and found that indeed ~25% of MAT{alpha} x MAT{alpha} matings did appear to result from such switches, leading to stable MATa/MAT{alpha} diploids.

However, most of the events were different and were often genetically unstable, giving rise to colonies with multiple phenotypes. Many matings arose from the creation of an at least transient a-like cell (presumably lacking expression of both MAT{alpha}1 and MAT{alpha}2), allowing it to mate with another {alpha}-mater. In some cases the resulting diploids were 2n-1 aneuploids that had lost the entire, presumably broken, chromosome. In many instances the diploids that were still heterozygous for markers distal to the MAT locus, but now {alpha}-mating. The most interesting group resulted in the loss of the all the markers distal to and including MAT{alpha}. Many of these colonies gave evidence of continuing genomic instability, with the loss of additional markers on chromosome III. Among nine stable derivatives we analyzed in detail, eight were homozygous for MAT{alpha} and more distal markers, but one contained a truncation of the right arm from at least MAT to the end of the chromosome. This last type was reminiscent of outcomes described in maize after the transposition of the Ds element. The truncation in yeast was one of the first examples of the apparent acquisition of a new telomere, either by de novo addition or by a nonreciprocal translocation. Before the days of genome sequencing, it was not possible to be more precise.

Viewed from today's perspective, we imagine that the diploids still heterozygous for the right arm repaired the chromosome break by gene conversion, becoming MAT{alpha}/MAT{alpha}. Those that became homozygous for the distal region likely resulted from break-induced replication (BIR, also known as recombination-dependent DNA replication) in which one end of the double-strand break (DSB) established a replication fork that could copy >100 kb to the end of the homologous, template chromosome (MORROW et al. 1997; KRAUS et al. 2001; DAVIS and SYMINGTON 2004; MALKOVA et al. 2005). It is also possible that some of the diploids showing loss of heterozygosity for markers distal to MAT arose from reciprocal exchanges accompanying gene conversion because we did not recover instances in which the distal regions became homozygous wild type.

In the same year that John McCusker examined MAT{alpha} x MAT{alpha} matings in heterothallic strains, Barbara Weiffenbach was studying similar genomic instability in homothallic strains (WEIFFENBACH and HABER 1981). MALONE and ESPOSITO (1980) had shown that MAT switching was lethal in the absence of the RAD52 recombination gene, suggesting that the process had similarities to the repair of X-ray-induced damage. It was not until 1982 that STRATHERN et al. (1982) showed that MAT switching did indeed involve a DSB. I had isolated a recessive mutation, swi1-1, that reduced, but did not eliminate, MAT switching (GARVIK and HABER 1977); hence we could study a population of MAT{alpha} rad52 cells in which several percent of the cells in each generation attempted to switch; such cells became a-like. This made it possible for us to examine newly generated broken chromosomes, importantly with all the breaks initiating at the same place. We mated these cells with a heterothallic MAT{alpha} strain and recovered diploids in which the broken chromosome was repaired by gene conversion, by BIR, or by new telomere addition. We again found that many of these diploids exhibited genomic instability, so that the colonies that arose were sectored for markers on chromosome III. Again, there were cases where the broken chromosome was completely lost and others in which there were stable outcomes in which markers distal to MAT were hemizyous or homozygous4.


MAKING AND BREAKING LINEAR DICENTRIC YEAST CHROMOSOMES
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About the same time we were analyzing chromosome breakage in a-like cells, we had isolated a circular chromosome in which the left and right arms were fused at HML and HMR. The fusion was bridged by an integrated plasmid, marked by URA3. Again, owing to what I had learned in preparation for teaching, I realized that we could replicate experiments in meiosis carried out in the 1930s by Lillian Morgan (MORGAN 1933) and Barbara McClintock (MCCLINTOCK 1938, 1939)! Morgan had recovered fruit fly progeny from a mother carrying a "ring" and a "rod" X chromosome, where a crossover would produce a dicentric chromosome. She inferred that such dicentrics were not recovered as viable progeny. In contrast, McClintock found that dicentrics generated in maize meiosis would rupture during meiotic divisions and produce gametes with broken chromosomes that subsequently produced cycles of BFB.

Our results in yeast (HABER and THORBURN 1984; HABER et al. 1984) proved to be different from those of both flies and maize. In meiosis, the dicentric chromosome did not break; instead, the entire dicentric chromosome was transmitted into a single spore, with URA3 marking the ring fusion and MAL2, distal to HMR, marking a sequence from the linear chromosome that was deleted in the ring (Figure 1). Apparently, in meiosis there is no true cytokinesis; instead, during the creation of four spores inside an ascus, there are apparently no forces strong enough to break a dicentric that is 300 kb long, each centromere pulled by single microtubules on a 6-µm spindle. In mitosis, by contrast, cytokinesis is accompanied by an actin-mediated rotation of the bud from the mother; I suspect that this mechanical event, and not spindle tension, breaks dicentrics, at least not when the two centromeres are separated by a long segment of DNA. And indeed, in mitotic cells derived from a spore carrying the dicentric, duplicated chromosome, there was frequent chromosome breakage. In fact, in mitotic cells we could demonstrate breakage and rearrangement of dicentric circular chromosomes arising from meiotic crossing over between two differently marked circular chromosomes. Thus even when the anaphase bridge is maintained by two equally long chromosome arms attached to the two centromeres, the mechanisms that can create chromosome breakage are robust. The situation is clearly different in maize, where the forces exerted on dicentric chromosomes by many microtubules or the length of the meiotic spindle are sufficient to break the chromosome in meiosis as well as in mitosis. Why dicentrics are trapped and eliminated in Drosophila meiosis is still not clear.


Figure 1
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FIGURE 1.—

Creating and breaking linear dicentric chromosomes in budding yeast. A circular chromosome III lacking MAL2 and other sequences distal to the fusion point is marked at the fusion by URA3. A crossover between linear and circular chromosomes in meiosis generates an unperturbed ring and an unchanged linear as well as a linear dicentric chromosome that carries a directly oriented ~300-kb duplication between two nonsister centromeres (circles). The dicentric is inherited intact into a spore without breakage (only three of four spores are viable), but subsequent breakage of the dicentric in mitotic cells leads to a variety of repair events. In the example shown, event A can occur intrachromosomally to recreate a recombined ring chromosome gentotypically distinct from the parental arrangement of markers. Event B must occur between two different broken chromatids that are both broken in mitosis and segregated to the same mitotic pole. The breaks in the two recombining partners need not be in the same location. Event C results from new telomere addition or the formation of a nonreciprocal translocation that stabilizes the broken chromosome. As many as seven different events could be recovered from a single spore carrying the entire dicentric chromosome.

 
Because the dicentric chromosome is essentially a tandem, direct duplication of most chromosome III sequences and heterozygous for a number of markers on the duplicated regions, a broken end could recombine with homologous sequences to produce either a linear or a circular derivative with a variety of genotypes (Figure 1). From spores carrying a dicentric chromosome we identified as many as seven different genotypes, with circular or linear "healed" chromosomes III. Importantly some derivatives had two different rearranged chromosomes that could arise if the replicated dicentric chromosomes each broke during mitosis and were repaired independently. Again, some outcomes appeared to involve nonreciprocal translocations or new telomere addition. At the time, using probes for the Y' subtelomeric region, we could demonstrate that some of the stable derivatives of dicentric breakage had new restriction fragments homologous to Y'. Whether these changes in telomere regions arose from genome shock, as MCCLINTOCK (1984) was fond of invoking, or represented the specific formation of nonreciprocal translocations that stabilized the end of chromosome III was beyond our ability to resolve at the time.

Twenty years later, with microarrays, DNA combing, and a complete knowledge of the genomic DNA sequence (PUTNAM et al. 2004; LEMOINE et al. 2005), it would be possible to determine the precise events that occurred in these cases. In 1984 we also could not be certain if there had been multiple BFB cycles as envisioned by McClintock. Direct evidence for such a cycle has come from recent articles analyzing the outcomes of dicentric breakage generated at fragile sites or eroding telomeres in budding yeast, by the presence of long inverted segments of chromosome arms (MARINGELE and LYDALL 2004; ADMIRE et al. 2006; NARAYANAN et al. 2006).


ANALYSIS OF SISTER CHROMATID EXCHANGE IN MEIOSIS
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One of the striking conclusions in MORGAN's (1933) study of meiosis involving a linear and a circular chromosome was that there were few meiotic crossovers involving sister chromatids relative to the number of exchanges between homologs. Morgan was able to deduce this by arguing that whereas a dicentric chromosome formed between a ring and a rod would eliminate an equal number of ring and rod-specific chromosome markers, crossovers between two sister ring chromosomes would eliminate two rings while sister exchange between linears would not prevent their recovery. Hence the degree of sister chromatid exchange could be deduced from the increased proportion of linear over circular products in fertile eggs. Morgan concluded that there was not much sister chromatid exchange in meiosis.

In budding yeast, dicentrics—even circular dicentrics formed by sister chromatid exchange between ring chromosomes—could be recovered and analyzed from the multiply sectored colonies produced by the spores. In addition, because yeast tetrads allow one to recover all four products of each meiosis, we could map the positions of all the crossovers between the ring and rod homologs. Our results were quite similar to those of Morgan's: in comparison to about three reciprocal crossovers per meiosis between the ring and rod homologous chromosomes (the number of crossovers in the ring x rod case was only slightly reduced from the number of crossovers between two linear chromosomes), only about one tetrad in eight had an exchange between sister chromatids. Later GAME et al. (1989) came to a similar conclusion by using chromosome-separating gels to measure directly the proportion of circular dicentric chromosomes.

A more controlled way of studying breakage of dicentric chromosomes was developed by Kerry Bloom, who showed that strong transcription across yeast's tiny centromere regions is sufficient to inactivate it. When transcription was turned off, the dicentric chromosome broke but could be repaired by nonhomologous end joinings (NHEJ) that could delete one of the two centromeres. We teamed up with Kerry Bloom to show that the number of complementary base pairs formed by joining these mechanically broken ends together was very similar to the NHEJ events that could repair an HO-induced DSB at the MAT locus in a rad52{Delta} strain (KRAMER et al. 1994). This was a very important experiment, as it showed that the treatment of HO-induced ends was not special. Still later, we realized we could study end joining in wild-type cells simply by deleting the HML and HMR donors (MOORE and HABER 1996). Using strains in which most cells failed to repair a single DSB also provided a way to study one important aspect of "genome shock"—the activation of the DNA damage checkpoint by ATM- and ATR-like kinases (SANDELL and ZAKIAN 1993; TOCZYSKI et al. 1997; LEE et al. 1998, 2000).

The legacy of Lillian Morgan and Barbara McClintock still echoes in more recent research in my lab, including the study of two different break-induced replication mechanisms that generate nonreciprocal translocations and also maintain chromosome ends in the absence of telomerase (LE et al. 1999; MALKOVA et al. 2001, 2005; DAVIS and SYMINGTON 2004). Recently we have also spent time in the company of McClintock's Ds element that provoked genomic instability in maize. WEIL and KUNZE (2000) expressed the maize Ac transposase in yeast and showed that it could cause the excision of a cloned Ds element. In collaboration with Cliff Weil's lab we showed that the ends left behind by the excision of Ds are hairpins and that they are normally opened up by the Mre11 endonuclease (YU et al. 2004). The opened hairpins are usually rejoined with the formation of palindromic nucleotide sequences that are one hallmark of V(D)J joints in the mammalian immune system. I imagine that mutants such as sae2{Delta} that prevent hairpin opening but do not prevent nonhomologous end joining should generate dicentric chromosomes by DNA replication, with a palindromic arrangement of sequences, as has recently been shown at inverted repeat sequences (NARAYANAN et al. 2006). It would be interesting to compare the outcomes to those we obtained 20 years ago. Whether some of the Ds-induced events in maize also resulted from a lack of hairpin opening after Ds excision would be interesting to know.

Looking back, I believe that much of this work would not have happened if I had not been first obliged, and then fascinated, to learn about analogous events that had been discovered 50 years before by two remarkable geneticists.


ACKNOWLEDGEMENTS
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I am indebted to Jeff Hall for his teaching me Drosophila and maize genetics. Scott Hawley, Michael Lichten, Kerry Bloom, and Andrès Aguilera offered very helpful comments on the manuscript. Research in my lab has been supported by grants from the National Institutes of Health (NIH), the National Science Foundation, the Department of Energy, and the Human Frontiers Science Program and by postdoctoral fellowships from the NIH, the American Cancer Society, Jane Coffin Childs Foundation, the Leukemia and Lymphoma Society, and the Medical Foundation of Boston, awarded to some of the creative young scientists with whom I have been privileged to work.


FOOTNOTES
2 I did take the first 3-week yeast genetics course at Cold Spring Harbor in 1970, memorably taught by Fred Sherman and Gerry Fink. I still remember being mystified by a lecture on gene conversion; but learning how to dissect tetrads and to score and maintain strains greatly lowered the energy barrier to undertaking genetic studies in my own lab. The Cold Spring Harbor Laboratory yeast course has been previously celebrated by SHERWOOD (2001). Back

3 That the lessons I was teaching in class had not penetrated very deeply into my own laboratory practice is seen from the fact that we isolated one allele of the first identified chromosome loss gene, CHL1 (HABER 1974; LIRAS et al. 1978), and did not think to get many more and do a complementation analysis. Later, KOUPRINA et al. (1993), using a similar chromosome loss assay, identified 18 such genes. Back

4 In 1993 we modified the rad52{Delta} MAT{alpha} strain by adding Tetrahymena telomere sequences centromere proximal to the site where HO-induced cleavage would produce an a-like phenotype. Kate Kramer showed that these sequences promoted new telomere formation, although as far as 100 bp distal to the Tetrahymena sequences. By sequencing the new telomeres, Kate was able to deduce the sequence of yeast telomerase RNA that was used to template the initially added telomere sequences (KRAMER and HABER 1993). Back


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