Figure 1

Proposed model for the functions of BLM helicase during DNA damage response. (A) DSBs (red line) are recognized after BLM and/or RAD51-stimulated RAD54-dependent chromatin remodeling. BLM affects chromatin organization by interacting with and regulating the function of CAF-1. On remodeled chromatin, BLM accumulates and helps in the optimal ATM activation and MRN complex accumulation. (B) MRN complex promotes H2AX phosphorylation (γH2AX, red dots) which recruits MDC1. MRN complex, stabilized on the DNA lesion by MDC1, promotes further accumulation of activated ATM. ATM phosphorylates MDC1 (purple dots), promoting the binding and recruitment of RNF8/Ubc13 complex, which catalyzes the Lys63-linked ubiquitylation of H2A and H2AX (yellow dots), causing a more accessible conformation of the chromatin. (C) RNF8/Ubc13 ubiquitylated histones recruits of RNF168. RNF168/Ubc13 attaches K63 linked polyubiquitin moieties to RNF8-ubiquitylated histones (yellow dots). (D) Poly-ubiquitylated histones recruits RAP80, which helps in the accumulation of Abraxas/BRCA1/BARD1 at DSBs. Constitutive methylation of histones H3 and H4 (blue dots) are probably exposed due to RNF168/Ubc13-dependent ubiquitylation. This results in the efficient recruitment of 53BP1 to the site of DNA damage. BLM again accumulates on the lesion in a 53BP1-dependent manner. Pro-recombinogenic proteins RAD51 and RAD54, interact with BLM, and accumulate at DSBs. (E) BLM functionally interacts with its partners like RAD51, RAD54, 53BP1 and p53 during HR. RAD51 binds to the single stranded DNA by displacing replication protein A (green dots). While BLM, 53BP1 and p53 have anti-recombinogenic property; BLM also has a pro-recombinogenic resection function in coordination with Exo1.