Time to bloom

Abstract

Bloom Syndrome (BS) is an autosomal recessive disorder due to mutation in Bloom helicase (referred in literature either as BLM helicase or BLM). Patients with BS are predisposed to almost all forms of cancer. BS patients are even today diagnosed in the clinics by hyper-recombination phenotype that is manifested by high rates of Sister Chromatid Exchange. The function of BLM as a helicase and its role during the regulation of homologous recombination (HR) is well characterized. However in the last few years the role of BLM as a DNA damage sensor has been revealed. For example, it has been demonstrated that BLM can stimulate the ATPase and chromatin remodeling activities of RAD54 in vitro. This indicates that BLM may increase the accessibility of the sensor proteins that recognize the lesion. Over the years evidence has accumulated that BLM is one of the earliest proteins that accumulates at the site of the lesion. Finally BLM also acts like a "molecular node" by integrating the upstream signals and acting as a bridge between the transducer and effector proteins (which again includes BLM itself), which in turn repair the DNA damage. Hence BLM seems to be a protein involved in multiple functions - all of which may together contribute to its reported role as a "caretaker tumor suppressor". In this review the recent literature documenting the upstream BLM functions has been elucidated and future directions indicated.

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.