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DNA interstrand cross-links (ICLs) pose a significant threat to genomic and cellular integrity by blocking essential cellular processes, including replication and transcription. In mammalian cells, much ICL repair occurs in association with DNA replication during S phase, following the stalling of a replication fork at the block caused by an ICL lesion. Here, we review recent work showing that the XPF-ERCC1 endonuclease and the hSNM1A exonuclease act in the same pathway, together with SLX4, to initiate ICL repair, with the MUS81-EME1 fork incision activity becoming important in the absence of the XPF-SNM1A-SLX4-dependent pathway. Another nuclease, the Fanconi anemia-associated nuclease (FAN1), has recently been implicated in the repair of ICLs, and we discuss the possible ways in which the activities of different nucleases at the ICL-stalled replication fork may be coordinated. In relation to this, we briefly speculate on the possible role of SLX4, which contains XPF and MUS81- interacting domains, in the coordination of ICL repair nucleases.

Original publication

DOI

10.4161/cc.10.23.18385

Type

Journal article

Journal

Cell Cycle

Publication Date

01/12/2011

Volume

10

Pages

3999 - 4008

Keywords

Animals, DNA, DNA Repair, DNA Replication, DNA-Binding Proteins, Endonucleases, Enzyme Activation, Exodeoxyribonucleases, Fanconi Anemia, Humans, Protein Structure, Tertiary, Recombinases, Replication Origin, Structure-Activity Relationship