FANC/BRCA1/BRCA2/ATM/NBS1 signaling pathway
The BASC
BRCA1 forms a multi-subunit protein complex referred to as the BRCA1-associated genome surveillance complex (BASC), which includes DNA damage repair proteins such as MSH2-MSH6 and MLH1, as well as ATM, NBS1, MRE11, and BLM.
BRCA1 is the protein defective in some cases of hereditary breast cancer susceptibility. The recent identification of RECQL3 as part of the BRCA1-associated genome surveillance complex (BASC), links RECQL3 with a number of tumour suppressor and DNA damage repair proteins.
The BASC complex includes MSH2, MHS6, MLH1, ATM, RECQL3, the RAD50-MRE11-NBS1 complex and DNA replication factor C.
Many components of this complex have roles in recognition of DNA damage/unusual DNA structures, suggestive of this complex performing some kind of ’sensor’ role.
To examine the role of RECQL3 within BASC, the subcellular localization of RECQL3 and BRCA1 was analysed before and after exposure to DNA damaging agents. In untreated cells, RECQL3 and BRCA1 colocalization was limited to a few bright nuclear foci.
However, after treatment with hydroxyurea or ionizing radiation, colocalization was greatly enhanced in those cells that were in mid-to-late S phase or in G2. This could be indicative of specific requirement for BLM/BRCA1 in replication/repair of late replicating DNA.
Consistent with a role for BLM (possibly within BASC) in recognizing abnormal DNA structures, it has been shown that RECQL3 is able to unwind a variety of unusual DNA structures, including G-quadruplex, synthetic X-junctions (models for the Holliday junction), bubbles and forked DNA.
Features
References
Venkitaraman AR. Tracing the network connecting BRCA and Fanconi anaemia proteins. Nat Rev Cancer. 2004 Apr;4(4):266-76. PMID: 15057286