Yonsei Med J.  2010 May;51(3):295-301. 10.3349/ymj.2010.51.3.295.

Multiple Roles of BRIT1/MCPH1 in DNA Damage Response, DNA Repair, and Cancer Suppression

• Lin SY
• Liang Y
• Li K

• KMID: 1074978
• DOI: http://doi.org/10.3349/ymj.2010.51.3.295

Abstract

Mammalian cells are frequently at risk of DNA damage from both endogenous and exogenous sources. Accordingly, cells have evolved the DNA damage response (DDR) pathways to monitor and assure the integrity of their genome. In cells, the intact and effective DDR is essential for the maintenance of genomic stability and it acts as a critical barrier to suppress the development of cancer in humans. Two central kinases for the DDR pathway are ATM and ATR, which can phosphorylate and activate many downstream proteins for cell cycle arrest, DNA repair, or apoptosis if the damages are irreparable. In the last several years, we and others have made significant progress to this field by identifying BRIT1 (also known as MCPH1) as a novel key regulator in the DDR pathway. BRIT1 protein contains 3 breast cancer carboxyl terminal (BRCT) domains which are conserved in BRCA1, MDC1, 53BP1, and other important molecules involved in DNA damage signaling, DNA repair, and tumor suppression. Our in vitro studies revealed BRIT1 to be a chromatin-binding protein required for recruitment of many important DDR proteins (ATM, MDC1, NBS1, RAD51, BRCA2) to the DNA damage sites. We recently also generated the BRIT1 knockout mice and demonstrated its essential roles in homologous recombination DNA repair and in maintaining genomic stability in vivo. In humans, BRIT1 is located on chromosome 8p23.1, where loss of hetero-zigosity is very common in many types of cancer. In this review, we will summarize the novel roles of BRIT1 in DDR, describe the relationship of BRIT1 deficiency with cancer development, and also discuss the use of synthetic lethality approach to target cancers with HR defects due to BRIT1 deficiency.

Keyword

DNA damage response; DNA repair; BRIT1; genomic instability; tumor suppressor

MeSH Terms

Animals
Chromosomal Proteins, Non-Histone/genetics/metabolism/*physiology
DNA Damage/genetics/*physiology
DNA Repair/genetics/*physiology
Humans
Mice
Models, Biological
Neoplasms/*genetics
Nerve Tissue Proteins/genetics/metabolism/*physiology

Figure

• 

  Fig. 1 The role of BRIT1 in DNA damage response. BRIT1 functions as a key DDR protein at multiple levels. Besides of its function in checkpoint and recruitment of many DDR proteins such as ATM, NBS1 and ATR to the damage sites, BRIT1 can modify the chromosome structure via interaction with SWI/SNF or Condensin II. It is also directly involved in DNA repair via interaction with RAD51/BRCA2.

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