XRCC1 mutation is associated with PARP1 hyperactivation and cerebellar ataxia
XRCC1 is a molecular scaffold protein that assembles multi-protein complexes involved in DNA single-strand break repair. Here we show that biallelic mutations in the human XRCC1 gene are associated with ocular motor apraxia, axonal neuropathy, and progressive cerebellar ataxia. Cells from a patient with mutations in XRCC1 exhibited not only reduced rates of single-strand break repair but also elevated levels of protein ADP-ribosylation. This latter phenotype is recapitulated in a related syndrome caused by mutations in the XRCC1 partner protein PNKP and implicates hyperactivation of poly(ADP-ribose) polymerase/s as a cause of cerebellar ataxia. Indeed, remarkably, genetic deletion of Parp1 rescued normal cerebellar ADP-ribose levels and reduced the loss of cerebellar neurons and ataxia in Xrcc1-defective mice, identifying a molecular mechanism by which endogenous single-strand breaks trigger neuropathology. Collectively, these data establish the importance of XRCC1 protein complexes for normal neurological function and identify PARP1 as a therapeutic target in DNA strand break repair-defective disease.
|Persistent URL||dx.doi.org/10.1038/nature20790, hdl.handle.net/1765/98904|
|Journal||Nature: international weekly journal of science|
Hoch, N.C. (Nicolas C.), Hanzlikova, H. (Hana), Rulten, S.L. (Stuart L.), Tétreault, M. (Martine), Komulainen, E. (Emilia), Ju, L, … Caldecott, K.W. (Keith W.). (2017). XRCC1 mutation is associated with PARP1 hyperactivation and cerebellar ataxia. Nature: international weekly journal of science, 541(7635), 87–91. doi:10.1038/nature20790