Emerging roles of BRIT1/MCPH1 in genome maintenance and tumor suppression

BRIT1 (BRCT-Repeat Inhibitor of hTERT expression) was originally identified from our laboratory as an inhibitor of human telomere reverse transcriptase (hTERT) by a genome-wide genetic screen[1]. The amino acid sequence of BRIT1 was later matched to a putative disease gene called microcephalin (MCPH1). Dysfunction of BRIT1/MCPH1 causes an autosomal recessive genetic disease known as primary microcephaly, which is characterized by reduced brain size of patients[2]. In addition to neuronal development disorder, aberrations of BRIT1 have been identified in various human cancers including breast, ovarian and prostate cancer. In order to gain the mechanistic insights into how BRIT1 deficiency leads to the pathogenesis of the human diseases, our studies and studies from other groups indicate BRIT1 functions as an early DNA damage responsive protein to coordinate cellular responses to genotoxic stresses and maintain genomic stability. In this chapter, we only focus on the function of BRIT1 as a tumor suppressor gene in tumorigenesis. We will discuss the emerging roles of BRIT1 in orchestrating cellular responses to DNA damage including DNA damage signaling, checkpoint activation, and DNA repair. As genomic instability is a hallmark of cancer cells, we will further discuss in the context of cancer development, how BRIT1 functions as a novel tumor suppressor by providing cells with a fundamental genome maintenance mechanism against tumorigenesis and how BRIT1 deficiency may provide a unique opportunity for targeted therapeutics in cancer treatment.