Small molecule inhibitors uncover synthetic genetic interactions of human flap endonuclease 1 (FEN1) with DNA damage response genes
Fig 2
Model for the repair of DNA double-strand breaks.
DSBs are recognised by the MRN complex (i.) which binds to the blunt DNA ends, holding them in close proximity. The exonuclease activity of MRE11A (or EXO1 in concert with BLM) is able to resect blunt ends, creating a 3’ ssDNA overhang, which becomes coated by the single-strand binding protein RPA (ii.), signalling for cell-cycle checkpoint arrest via ATR. RPA is displaced by RAD51 (iii.) to allow for HR. Alternatively, the MRN complex can be replaced by KU78/KU80 complex (iv.), protecting DNA ends from resection and promoting NHEJ through the binding of the DNA-PK catalytic subunit (DNA-PKcs). DSBs formed as a consequence of replication fork collapse require HR for their repair. Fork stalling, following replication stress for example, activates the FA pathway in an attempt to stabilise and protect the fork (v.). The FA core complex recognises the stalled fork and ubiquitinates the FANCD2-FANCI heterodimer. Stalled forks can be further processed by structure selective endonucleases to restore the replication fork (vi.) or cleave the fork to produce a DSB (vii.). Alternatively, the post-replication machinery can bypass damaged bases at stalled forks. One such pathway leads to template switching in a HR-mediated pathway.