BLM is a member of the RecQ family of DNA helicases. Germline mutations in BLM and other members of the RecQ helicase family, WRN and RECQ4, result in autosomal-recessive disorders, Bloom syndrome (BS), Werner Syndrome (WS) and Rothmund-Thomson syndrome (RTS) respectively. These syndromes are rare autosomal-recessive disorders that are associated with elevated incidence of cancer. The BS afflicted individuals are predisposed to most types of cancers. Cancer affects about new 700,000 cases every year in India and results in 350,000 deaths per year. BLM is thought to be a """"""""caretaker tumor suppressor"""""""" involved in suppressing neoplastic transformation by controlling chromosomal stability. BLM has been proposed to function at the interface of replication and recombination, and to facilitate the repair of DNA damage. Many similar caretakers functionally interact with BLM, thereby indicating a concerted attempt by the various tumor suppressors to maintain genomic stability. Conversely loss of functional interaction of BLM with the other tumor suppressors can lead to enhanced instability of the genome. Inactivation of tumor suppressor, p53, in BS cells causes a significant increase of homologous recombination (HR) compared with BS cells alone, thereby demonstrating that p53 and BLM cooperatively affect HR. Though the downstream effects of BLM on DNA repair and recombination are better characterized, not much information is available about how the signal is transmitted to BLM from the sites of DNA damage. Hence in Module A, I will study the specific role of Chk1-mediated phosphorylation on BLM function(s). The two specific aims of this module are: 1. Determining the Chk1-mediated phosphorylation site(s) of BLM; 2. Functional consequences of Chk1 mediated phosphorylation of BLM. Studies have not yet conclusively deciphered whether and, if so how, BLM modulates HR in combination with other proteins involved in the process. Hence in Module B, I will investigate whether BLM regulates HR in combination with proteins involved in signal transduction like 53BP1.
The specific aims of this module are: 1. Mechanistic analysis of the interaction between BLM and 53BP1 during replication stress; 2. Determine the functional consequence of BLM interaction with 53BP1 during homologous recombination. ? ? ?
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