The maintenance of genome integrity is essential to all life, but is particularly important to long-lived multicellular organisms, which are susceptible to cancer. DNA damage can take the form of base modifications, strand breaks, interstrand cross-links and other lesions. To deal with many types of damage, genomes have evolved multiple cellular defense mechanisms, including DNA repair and cell cycle checkpoint processes. Different pathways exist for specific kinds of DNA damage and the cell must have ways to decide which mechanism to use for a given lesion. These requirements imply that signaling networks not only sense the presence of DNA damage, but also receive specific input such as the chemical nature of the damage, the timing of the cell cycle, the type of cell and the location of damage on the DNA. BASC (BRCA1-Associated Genome Surveillance Complex), a super complex of BRCA1 (Breast Cancer Susceptibility Protein-1), is key to recognizing and repairing DNA damage. This complex includes tumor suppressors and DNA damage repair proteins MSH2, MSH6, MLH1, ATM (Ataxia-Telangiectasia), BLM (Bloom syndrome), and the Rad50-MRE11 (Meiotic Recombination-11)-NBS1 (Nijmegen Breakage Syndrome) protein complex. In addition, RFC (DNA Replication Factor-C), a protein complex that facilitates the loading of PCNA onto DNA, is also part of BASC (Ref.1 & 2). References 1.FANCD2: a branch-point in DNA damage response? Grompe M. Nat Med. 2002 Jun;8(6): 555-6. No abstract available. Wang Y, Cortez D, Yazdi P, Neff N, Elledge SJ, Qin J. Genes Dev. 2000 Apr 15;14(8):927-39. Pang Q, Keeble W, Christianson TA, Faulkner GR, Bagby GC. EMBO J. 2001 Aug 15; 20(16): 4478-89. 4.Biallelic inactivation of BRCA2 in Fanconi anemia. Howlett NG, Taniguchi T, Olson S, Cox B, Waisfisz Q, De Die-Smulders C, Persky N, Grompe M, Joenje H, Pals G, Ikeda H, Fox EA, D'Andrea AD. Science. 2002 Jul 26; 297(5581): 606-9. 5.Molecular pathogenesis of Fanconi anemia: recent progress. Taniguchi T, D'Andrea AD. Blood. 2006 Jun 1;107(11):4223-33. Epub 2006 Feb 21. 6.Heterogeneity in Fanconi anemia: evidence for 2 new genetic subtypes. Levitus M, Rooimans MA, Steltenpool J, Cool NF, Oostra AB, Mathew CG, Hoatlin ME, Waisfisz Q, Arwert F, de Winter JP, Joenje H. Blood. 2004 Apr 1;103(7):2498-503. Epub 2003 Nov 20. 7.Biallelic inactivation of BRCA2 in Fanconi anemia. Howlett NG, Taniguchi T, Olson S, Cox B, Waisfisz Q, De Die-Smulders C, Persky N, Grompe M, Joenje H, Pals G, Ikeda H, Fox EA, D'Andrea AD. Science. 2002 Jul 26; 297(5581): 606-9. 8.Enhancement of BRCA1 E3 ubiquitin ligase activity through direct interaction with the BARD1 protein. Xia Y, Pao GM, Chen HW, Verma IM, Hunter T. J Biol Chem. 2003 Feb 14;278(7):5255-63. Epub 2002 Nov 12. 9.Constitutive association of BRCA1 and c-Abl and its ATM-dependent disruption after irradiation. Foray N, Marot D, Randrianarison V, Venezia ND, Picard D, Perricaudet M, Favaudon V, Jeggo P. Mol Cell Biol. 2002 Jun; 22(12): 4020-32. 10.Autoubiquitination of the BRCA1*BARD1 RING ubiquitin ligase. Chen A, Kleiman FE, Manley JL, Ouchi T, Pan ZQ. J Biol Chem. 2002 Jun 14; 277(24): 22085-92. Epub 2002 Apr 01. 11.The Fanconi anaemia/BRCA pathway. D'Andrea AD, Grompe M. Nat Rev Cancer. 2003 Jan; 3(1): 23-34. Review. 12.BRCA1 regulates GADD45 through its interactions with the OCT-1 and CAAT motifs. Fan W, Jin S, Tong T, Zhao H, Fan F, Antinore MJ, Rajasekaran B, Wu M, Zhan Q. J Biol Chem. 2002 Mar 8;277(10):8061-7. Epub 2002 Jan 3. 13.BRCA1 physically and functionally interacts with ATF1. Houvras Y, Benezra M, Zhang H, Manfredi JJ, Weber BL, Licht JD. J Biol Chem. 2000 Nov 17;275(46):36230-7. 14.BRCA1-associated growth arrest is RB-dependent. Aprelikova ON, Fang BS, Meissner EG, Cotter S, Campbell M, Kuthiala A, Bessho M, Jensen RA, Liu ET. Proc Natl Acad Sci U S A. 1999 Oct 12;96(21):11866-71. 15.Activation of the E3 ligase function of the BRCA1/BARD1 complex by polyubiquitin chains. Mallery DL, Vandenberg CJ, Hiom K. EMBO J. 2002 Dec 16; 21(24): 6755-62. |