Regulation of Oxidized Base Repair in Human Chromatin by Posttranslational Modification

Base excision repair (BER) is the major pathway for the repair of oxidized bases and apurinic/apyrimidinic (abasic; AP) sites produced by reaction with reactive oxygen/nitrogen species (ROS/RNS). These metabolites are generated spontaneously by endogenous cellular processes and also by environmental agents. Because most of these lesions are promutagenic, linked to diverse disease-associated somatic mutations, as well as heritable single nucleotide polymorphisms (SNPs) in the normal human population, their prompt repair is warranted. Impairment of repair leading to mutation, a hallmark of cancer, underscores the essentiality of BER for maintaining genome integrity in humans and other mammals. In mammals, repair of oxidized bases and other BER substrates is initiated by DNA glycosylases (DGs), which excise the damaged bases and cleave the DNA strands at the resulting AP sites, followed by sequential end processing, gap-filling DNA synthesis, and ligation. In vitro BER performed with naked DNA substrates has been extensively studied, which delineates its basic mechanistic steps and subpathways. However, recent interest is directed to unraveling BER in cell chromatin, including its regulation via posttranslational modifications (PTMs), which occurs possibly in concert with nucleosome remodeling. Emerging reports on various PTMs of BER enzymes indicate that the PTMs, while dispensable for the enzymatic activity, regulate overall repair by modulating interactions with other repair proteins and chromatin factors, assembly of BER complexes, as well as turnover of the proteins, and may ultimately dictate the cellular phenotype. Here, we discuss recent advances in the BER field by reviewing the PTMs and how they regulate BER in chromatin

Mutant FUS causes DNA ligation defects to inhibit oxidative damage repair in Amyotrophic Lateral Sclerosis

Genome damage and defective repair are etiologically linked to neurodegeneration. However, the specific mechanisms involved remain enigmatic. Here, we identify defects in DNA nick ligation and oxidative damage repair in a subset of amyotrophic lateral sclerosis (ALS) patients. These defects are caused by mutations in the RNA/DNA-binding protein FUS. In healthy neurons, FUS protects the genome by facilitating PARP1-dependent recruitment of XRCC1/DNA Ligase IIIα (LigIII) to oxidized genome sites and activating LigIII via direct interaction. We discover that loss of nuclear FUS caused DNA nick ligation defects in motor neurons due to reduced recruitment of XRCC1/LigIII to DNA strand breaks. Moreover, DNA ligation defects in ALS patient-derived iPSC lines carrying FUS mutations and in motor neurons generated therefrom are rescued by CRISPR/Cas9-mediated correction of mutation. Our findings uncovered a pathway of defective DNA ligation in FUS-linked ALS and suggest that LigIII-targeted therapies may prevent or slow down disease progression.status: publishe