{alpha}-N-Methylation of Damaged DNA-Binding Protein 2 (DDB2) and Its Function in Nucleotide Excision Repair [Genomics and Proteomics]

April 21st, 2014 by Cai, Q., Fu, L., Wang, Z., Gan, N., Dai, X., Wang, Y.

DDB2 exhibits a high affinity toward UV-damaged DNA and it is involved in the initial steps of global genome nucleotide excision repair (GG-NER). Mutations in the DDB2 gene cause the genetic complementation group E of xeroderma pigmentosum (XPE), an autosomal recessive disease manifested clinically by hypersensitivity to sunlight exposure and an increased predisposition to skin cancer. Here, we found that, in human cells, the initiating methionine residue in DDB2 was removed and the N-terminal alanine could be methylated on its α-amino group in human cells, with trimethylation being the major form. We also demonstrated that the α-N-methylation of DDB2 is catalyzed by the N-terminal RCC1 methyltransferase (NRMT). In addition, a methylation-defective mutant of DDB2 displayed diminished nuclear localization and was recruited at a reduced efficiency to UV-induced cyclobutane pyrimidine dimer (CPD) foci. Moreover, loss of this methylation conferred compromised ATM activation, decreased efficiency in CPD repair, and elevated sensitivity of cells toward UV light exposure. Together, our study provided new knowledge about the post-translational regulation of DDB2 and expanded the biological functions of protein α-N-methylation to DNA repair.