Abstract
CtIP is involved in the resection of broken DNA during the S and G2 phases of the cell cycle for repair by recombination. Acting with the MRN complex, it plays a particularly important role in handling complex DNA end structures by localised nucleolytic processing of DNA termini in preparation for longer range resection. Here we show that human CtIP is a tetrameric protein adopting a dumbbell architecture in which DNA binding domains are connected by long coiled-coils. The protein complex binds two short DNA duplexes with high affinity and bridges DNA molecules in trans. DNA binding is potentiated by dephosphorylation and is not specific for DNA end structures per se. However, the affinity for linear DNA molecules is increased if the DNA terminates with complex structures including forked ssDNA overhangs and nucleoprotein conjugates. This work provides a biochemical and structural basis for the function of CtIP at complex DNA breaks.
Highlights
DNA double-strand breaks (DSBs) are a potentially lethal form of DNA damage associated with genomic instability, gross chromosomal rearrangements and apoptosis (Ranjha et al, 2018)
DSBs are repaired by two major pathways: homologous recombination (HR) and non-homologous end-joining (NHEJ)
The predominance of either pathway is regulated in a cell cycle-dependent manner owing to the requirement for a sister chromatid to act as a template for error-free repair
Summary
DNA double-strand breaks (DSBs) are a potentially lethal form of DNA damage associated with genomic instability, gross chromosomal rearrangements and apoptosis (Ranjha et al, 2018). They are caused by exogenous agents such as ionising radiation (IR) and chemotherapeutic drugs, and by normal cell metabolism such as during V(D)J/class-switch recombination, Spo11-mediated meiotic recombination, or replication fork collapse. DSBs are preferentially degraded by nucleases to reveal long 30-ssDNA overhangs (Cejka, 2015; Daley et al, 2015) These are stabilised by RPA and bound by Rad, which forms nucleoprotein filaments that undergo strand invasion with the sister chromatid, eventually leading to DNA repair without loss of genetic information (Kowalczykowski, 2015).
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