Abstract
Efficient DNA double strand break (DSB) repair by homologous recombination (HR), as orchestrated by histone and non-histone proteins, is critical to genome stability, replication, transcription, and cancer avoidance. Here we report that Heterochromatin Protein1 beta (HP1β) acts as a key component of the HR DNA resection step by regulating BRCA1 enrichment at DNA damage sites, a function largely dependent on the HP1β chromo shadow domain (CSD). HP1β itself is enriched at DSBs within gene-rich regions through a CSD interaction with Chromatin Assembly Factor 1 (CAF1) and HP1 β depletion impairs subsequent BRCA1 enrichment. An added interaction of the HP1 β CSD with the Polycomb Repressor Complex 1 ubiquitinase component RING1A facilitates BRCA1 recruitment by increasing H2A lysine 118-119 ubiquitination, a marker for BRCA1 recruitment. Our findings reveal that HP1β interactions, mediated through its CSD with RING1A, promote H2A ubiquitination and facilitate BRCA1 recruitment at DNA damage sites, a critical step in DSB repair by the HR pathway. These collective results unveil how HP1β is recruited to DSBs in gene-rich regions and how HP1β subsequently promotes BRCA1 recruitment to further HR DNA damage repair by stimulating CtIP-dependent resection.
Competing Interest Statement
The authors have declared no competing interest.
Footnotes
Authors e-mail address: Vijay K. Charaka: vkcharaka{at}houstonmethodist.org
Sharmistha Chakraborty: sharmisthachakraborty70{at}gmail.com
Chi Lin Tsai: ctsai5{at}mdanderson.org
Xiaoyan Wang: xiaoyan.wang2016{at}outlook.com
Raj K. Pandita: rkp_jalali{at}yahoo.com
John A. Tainer: jtainer{at}mdanderson.org
Clayton R Hunt: crhunt305{at}gmail.com
Tej K. Pandita: tejkrishnanpandita{at}gmail.com; tej.pandita{at}BCM.edu; tpandita{at}tamu.edu
Authors have no conflict of interest