Selected publications

• Wang Anderson T, Sengerova Blanka, Cattell Emma, Inagawa Takabumi, Hartley Janet M, Kiakos Konstantinos, Burgess-Brown Nicola A, Swift Lonnie P, Enzlin Jacqueline H, Schofield Christopher J, Gileadi Opher, Hartley John A, and McHugh Peter J (2011) Human SNM1A and XPF-ERCC1 collaborate to initiate DNA interstrand cross-link repair. Genes Dev, 25(17):1859-70.

• Sengerova Blanka, Wang Anderson T, and McHugh Peter J (2011) Orchestrating the nucleases involved in DNA interstrand cross-link (ICL) repair. Cell Cycle, 10(23):3999-4008.

• Tafel Agnieszka A, Wu Leonard, and McHugh Peter J (2011) Human HEL308 localizes to damaged replication forks and unwinds lagging strand structures. J Biol Chem, 286(18):15832-40.

• Sarkar Sovan, Kiely Rhian, and McHugh Peter J (2010) The Ino80 chromatin-remodeling complex restores chromatin structure during UV DNA damage repair. J Cell Biol, 191(6):1061-8.

• Bhagwat Nikhil, Olsen Anna L, Wang Anderson T, Hanada Katsuhiro, Stuckert Patricia, Kanaar Roland, D'Andrea Alan, Niedernhofer Laura J, and McHugh Peter J (2009) XPF-ERCC1 participates in the Fanconi anemia pathway of cross-link repair. Mol Cell Biol, 29(24):6427-37.

Peter McHugh

DNA interstrand cross-links (ICLs) are produced when the two strands of the double-helix become covalently linked. ICLs are an extremely toxic form of DNA damage that inhibit fundamental cellular processes such as DNA replication and transcription.  Defects in ICL repair are associated with cancer pre-disposition syndromes, as exemplified by Fanconi anemia. Moreover, many important cancer chemotherapeutics exert their cytotoxic effects by ICL formation. Consequently, understanding ICL repair is important for improving both cancer prevention and treatment strategies.  A major goal of this laboratory is to define the DNA repair pathways acting on interstrand cross-links. We have historically focused on the yeast Saccharomyces cerevisiae as a model system to understand these pathways, but more recently have begun to translate our findings into studies of human cells and also initiated biochemical studies of the proteins involved.

One of the major repair responses to ICLs in mammalian cells is triggered by the collision of DNA replication forks with ICLs.  This so-called ‘replication-coupled ICL repair’ involves several structure-specific endonucleases including XPF-ERCC1, Mus81-Eme1 as well as helicases, including HEL308, although the details and sequence of events in this pathway remain poorly understood.  We have recently made some significant progress in delineating the basic mechanism of replication-associated ICL repair in human cells. Our results indicate that two key, related nucleases, XPF and Mus81 act in temporally distinct ICL repair pathways during replication.  We have shown that XPF is a strong candidate for mediating the initial incisions of ICLs, releasing the linkage of the two DNA strands.  We are now working to identify and characterize further factors involved in this repair pathway.

Related to our ICL repair studies, we also have a major interest in a family of DNA repair factors that contain a metallo-beta-lactamase structural domain. These factors, including the yeast Pso2 and human Snm1A and SNM1B exonucleases, play an important role in the post-incision processing of cross-link repair intermediates. Recent studies from our group suggest that this family of proteins might act to digest ICL repair intermediates produced after the initial incisions are made, permitting downstream repair reactions (Fig. 1).  Detailed genetic, biochemical and cell biological studies of this family of protein are ongoing in our laboratory.

 

 Fig 1

Model for the role of human SNM1A in ICL repair. Following incision and release of the crosslink by XPF-ERCC1, the hSNM1A protein degrades the residual tethered oligonucleotide to promote downstream repair events and replication restart.