BRIT1/MCPH1: A Guardian of Genome and an Enemy of Tumors

Abstract

The DNA of every cell is constantly exposed to insult mediated by endogenous and environmental factors that induced damage in its structure. To react to these attacks and maintain the integrity of the genome, eukaryotic cells are equipped with sophisticated mechanisms to detect, signal the presence of and repair DNA damage. The cellular response to DNA damage is a critical event for maintaining genomic stability and limiting neoplastic transformation. BRIT1, a newly identified protein, forms specific irradiation-induced nuclear foci. Our recent investigation demonstrates that BRIT1 functions as a proximal factor in the DNA damage checkpoints that control multiple damage sensors and early mediators. BRIT1 is also implicated in cell cycle checkpoints, controlling and regulating other important molecules and thus affecting the timing of mitosis. Depletion of BRIT1 abolishes the DNA damage response and results in centrosomal abnormalities and chromosomal aberrations. Moreover, aberrantly reduced expression of BRIT1 in human carcinomas implicates this protein in cancer initiation and progression. Together, the findings identify BRIT1 as a potential tumor suppressor. Fully elucidating the function of this intriguing protein may lead to new therapeutic approaches for the improved cancer treatment.

Cytokinesis and cancer

“…Also, BRIT1 has been shown to correlate with the occurrence of metastasis, suggesting that it might contribute to tumour aggressiveness. All these data indicate the importance of BRIT1 defects in cancer progression [67].…”

Dual recognition of phosphoserine and phosphotyrosine in histone variant H2A.X by DNA damage response protein MCPH1

“…MCPH1 is implicated in chromatin remodeling by virtue of its interaction with the SWI/SNF complex (15), in signaling programs via its association with Chk1 among other proteins (11,(29)(30)(31)(32), and aids the DNA repair process by interacting with BRCA2 (33) and Condensin II (34,35). Because of its involvement in multiple processes that converge to maintain genomic integrity, MCPH1 has been termed a "guardian of the genome" (13). Indeed, ablation of MCPH1 resulted in a menagerie of chromosomal defects that includes changes in both the nature and number of chromosomes, highlighting its importance in regulating genomic stability (12,13).…”

“…Because of its involvement in multiple processes that converge to maintain genomic integrity, MCPH1 has been termed a "guardian of the genome" (13). Indeed, ablation of MCPH1 resulted in a menagerie of chromosomal defects that includes changes in both the nature and number of chromosomes, highlighting its importance in regulating genomic stability (12,13). Furthermore, diminished DNA copy numbers as well as reduced MCPH1 mRNA and protein expression levels have been noted in several breast and ovarian cell lines and in ovarian cancer tissues, suggesting that MCPH1 is a putative tumor suppressor (12).…”

“…Microcephalin (MCPH1), the first gene identified as causative for primary autosomal microcephaly (10), has been linked to various cellular processes including the DNA damage checkpoint, DNA repair by homologous recombination, and DNA transcription (11)(12)(13)(14)(15). Previous studies have established that MCPH1 is an early responder in the DNA damage response (DDR) and regulates the recruitment of several downstream mediator proteins, a characteristic shared with MDC1.…”

DNA Damage Response and Breast Cancer: An Overview

“…ATM and ATR act on BRIT, However, BRIT is NOT required to phosphorylate ATM but is needed to recruit pATM to the damaged DNA and also www.intechopen.com positively regulates CHK1 and BRCA-1 expression. BRIT binds to chromatin and forms nuclear foci after exposure to ionizing radiation or UV rays as short as 2 minutes after the radiation occurs (Chaplet et al, 2006). This chromosome region is frequently deleted in breast, ovarian and prostate cancers.…”