Role of CTCF in DNA damage response

Abstract

CCCTC-binding factor (CTCF) is a highly conserved, ubiquitously expressed zinc finger protein. CTCF is a multifunctional protein, associated with a number of vital cellular processes such as transcriptional activation, repression, insulation, imprinting and genome organization. Emerging evidence indicates that CTCF is also involved in DNA damage response. In this review, we focus on the newly identified role of CTCF in facilitating DNA double-strand break repair. Due to the large number of cellular processes in which CTCF is involved, factors that functionally affect CTCF could have serious implications on genomic stability. It is becoming increasingly clear that exposure to environmental toxicants could have adverse effects on CTCF functions. Here we discuss the various ways that environmental toxicants could impact CTCF functions and the potential consequences on DNA damage response.

Keywords: CTCF; Cohesin; DNA double-strand breaks; Environmental toxicants; Nickel; γH2AX.

Fig. 1. CTCF establishes γH2AX domains during DSB repair

Upon DNA damage, CTCF binds DSBs and facilitates γH2AX domains formation by functioning as domain barrier. Cohesin likely interacts with CTCF during γH2AX foci and nano-foci establishment. Cohesin binding at the promoters of active genes within domains inhibit γH2AX establishment, thereby protecting transcription. Loss of cohesin binding at gene promoters cause γH2AX spreading and gene silencing. CTCF depletion causes loss of higher-order chromatin structures resulting in spreading of γH2AX foci and impaired DNA repair. Green arrow: active gene; red arrow: repressed gene

Fig. 2. CTCF recruits BRCA2 to DSB during HR

During DSB repair, CTCF recruits BRCA2 to DSBs in a PARlation dependent manner. BRCA2 in turn recruits RAD 51, which form filaments to allow strand invasion and homologous recombination.

Fig. 3

Environmental exposures could functionally impact CTCF in multiple ways and potentially impair DNA repair function.