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SPINDOC binds PARP1 to facilitate PARylation

Fen Yang, Jianji Chen, Bin Liu, Guozhen Gao, Manu Sebastian, Collene Jeter, Jianjun Shen, Maria D. Person and Mark T. Bedford ()
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Fen Yang: The University of Texas MD Anderson Cancer Center
Jianji Chen: The University of Texas MD Anderson Cancer Center
Bin Liu: The University of Texas MD Anderson Cancer Center
Guozhen Gao: The University of Texas MD Anderson Cancer Center
Manu Sebastian: The University of Texas MD Anderson Cancer Center
Collene Jeter: The University of Texas MD Anderson Cancer Center
Jianjun Shen: The University of Texas MD Anderson Cancer Center
Maria D. Person: Center for Biomedical Research Support The University of Texas at Austin
Mark T. Bedford: The University of Texas MD Anderson Cancer Center

Nature Communications, 2021, vol. 12, issue 1, 1-15

Abstract: Abstract SPINDOC is tightly associated with the histone H3K4me3 effector protein SPIN1. To gain a better understanding of the biological roles of SPINDOC, we identified its interacting proteins. Unexpectedly, SPINDOC forms two mutually exclusive protein complexes, one with SPIN1 and the other with PARP1. Consistent with its ability to directly interact with PARP1, SPINDOC expression is induced by DNA damage, likely by KLF4, and recruited to DNA lesions with dynamics that follows PARP1. In SPINDOC knockout cells, the levels of PARylation are reduced, in both the absence and presence of DNA damage. The SPINDOC/PARP1 interaction promotes the clearance of PARP1 from damaged DNA, and also impacts the expression of known transcriptional targets of PARP1. To address the in vivo roles of SPINDOC in PARP1 regulation, we generate SPINDOC knockout mice, which are viable, but slightly smaller than their wildtype counterparts. The KO mice display reduced levels of PARylation and, like PARP1 KO mice, are hypersensitive to IR-induced DNA damage. The findings identify a SPIN1-independent role for SPINDOC in the regulation of PARP1-mediated PARylation and the DNA damage response.

Date: 2021
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DOI: 10.1038/s41467-021-26588-y

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