Journal
MOLECULAR AND CELLULAR BIOLOGY
Volume 38, Issue 3, Pages -Publisher
AMER SOC MICROBIOLOGY
DOI: 10.1128/MCB.00489-17
Keywords
mitochondria; genome integrity; RAD51 paralogs; replication stress; POLG
Categories
Funding
- Department of Science and Technology [EMR/2015/001720]
- Department of Biotechnology (DBT) [BT/PR5846/BRB/10/1099/2012]
- IISc-DBT partnership program [DBT/BF/PR/INS/IISc/2011-12]
- DST-FIST
- UGC
- DBT
- IISc
Ask authors/readers for more resources
Mechanisms underlying mitochondrial genome maintenance have recently gained wide attention, as mutations in mitochondrial DNA (mtDNA) lead to inherited muscular and neurological diseases, which are linked to aging and cancer. It was previously reported that human RAD51, RAD51C, and XRCC3 localize to mitochondria upon oxidative stress and are required for the maintenance of mtDNA stability. Since RAD51 and RAD51 paralogs are spontaneously imported into mitochondria, their precise role in mtDNA maintenance under unperturbed conditions remains elusive. Here, we show that RAD51C/XRCC3 is an additional component of the mitochondrial nucleoid having nucleus-independent roles in mtDNA maintenance. RAD51C/XRCC3 localizes to the mtDNA regulatory regions in the D-loop along with the mitochondrial polymerase POLG, and this recruitment is dependent upon Twinkle helicase. Moreover, upon replication stress, RAD51C and XRCC3 are further enriched at the mtDNA mutation hot spot region D310. Notably, the absence of RAD51C/XRCC3 affects the stability of POLG on mtDNA. As a consequence, RAD51C/XRCC3-deficient cells exhibit reduced mtDNA synthesis and increased lesions in the mitochondrial genome, leading to overall unhealthy mitochondria. Together, these findings lead to the proposal of a mechanism for a direct role of RAD51C/XRCC3 in maintaining mtDNA integrity under replication stress conditions.
Authors
I am an author on this paper
Click your name to claim this paper and add it to your profile.
Reviews
Recommended
No Data Available