FHA domain of yeast Xrs2, a homologue of human Nbs1, promotes non-homologous end joining through the interaction with a Ligase IV partner protein, Lif1
Kenichiro Matsuzaki 1, Akira Shinohara 1 and Miki Shinohara 1*
1 Osaka University
* To whom correspondence should be addressed. E-mail: mikis{at}protein.osaka-u.ac.jp.
Submitted on July 23, 2007
Revised on August 17, 2007
Accepted on 14 February 2008
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Abstract |
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DNA double-strand breaks (DSB) are repaired through two different pathways, homologous recombination (HR) and non-homologous end-joining (NHEJ). Yeast Xrs2, a homologue of human Nbs1, is a component of the Mre11-Rad50-Xrs2 (MRX) complex required for both HR and NHEJ. Previous studies showed that the N-terminus FHA domain of Xrs2/Nbs1 in yeast is not involved in HR, but is likely to be in NHEJ. In this study, we showed that the FHA domain of Xrs2 plays a critical role in efficient DSB repair by NHEJ. The FHA domain of Xrs2 specifically interacts with Lif1, a component of the ligase-IV complex, Dnl4-Nej1-Lif1 (DNL). Lif1, which is phosphorylated in vivo, contains two Xrs2-binding regions. Serine 383 of Lif1 plays an important role in the interaction with Xrs2 as well as in NHEJ. Interestingly, the phospho-mimetic substitutions of Serine-383 enhance the NHEJ activity of Lif1. Our results suggest that the phosphorylation of Lif1 at Serine-383 is recognized by the Xrs2 FHA domain, which in turn may promotes recruitment of the DNL complex to DSB for NHEJ. The interaction between Xrs2 and Lif1 through the FHA domain is conserved in human; FHA domain Nbs1 interacts with Xrcc4, a Lif1 homologue of human.
Key Words:
DNA double-strand break repair, MRX, NHEJ
