Facilitation of base excision repair by chromatin remodeling

Abstract

Base Excision Repair (BER) is a conserved, intracellular DNA repair system that recognizes and removes chemically modified bases to insure genomic integrity and prevent mutagenesis. Aberrant BER has been tightly linked with a broad spectrum of human pathologies, such as several types of cancer, neurological degeneration, developmental abnormalities, immune dysfunction and aging. In the cell, BER must recognize and remove DNA lesions from the tightly condensed, protein-coated chromatin. Because chromatin is necessarily refractory to DNA metabolic processes, like transcription and replication, the compaction of the genomic material is also inhibitory to the repair systems necessary for its upkeep. Multiple ATP-dependent chromatin remodelling (ACR) complexes play essential roles in modulating the protein-DNA interactions within chromatin, regulating transcription and promoting activities of some DNA repair systems, including double-strand break repair and nucleotide excision repair. However, it remains unclear how BER operates in the context of chromatin, and if the chromatin remodelling processes that govern transcription and replication also actively regulate the efficiency of BER. In this review we highlight the emerging role of ACR in regulation of BER.

Nucleolin and nucleophosmin: nucleolar proteins with multiple functions in DNA repair

“…given that chromatin remodeling is known to be a major factor in the activities of all DNA repair D r a f t 30 pathways it is possible that histone chaperoning by NCL and NPM1 may in the future be recognized as regulatory activities contributing to their role(s) in other DDR and non-DDR pathways (Dinant et al 2012;Hinz and Czaja 2015;Jeggo and Downs 2014;Li 2014).…”

Genome-wide maps of alkylation damage, repair, and mutagenesis in yeast reveal mechanisms of mutational heterogeneity

“…In vitro studies using purified BER enzymes have shown that each step in the BER pathway is significantly inhibited within a strongly positioned nucleosome, particularly when the lesion has an inward rotational setting or translational position near the nucleosome dyad (i.e., the position of intersection of DNA with the central dyad axis of the nucleosome) (Rodriguez et al 2015). However, it is not clear to what extent nucleosomes affect BER in vivo, since nucleosome positioning in eukaryotic genomes is generally weaker than the positioning sequences used for in vitro studies (Mao et al 2017) and the presence of cellular chromatin-remodeling enzymes can facilitate BER in nucleosomes (Hinz and Czaja 2015;Rodriguez et al 2015). Moreover, nucleosomes in vivo are marked by different histone post-translational modifications, which could potentially alter repair efficiency (Rodriguez et al 2016).…”

Regulation of Oxidized Base Repair in Human Chromatin by Posttranslational Modification

“…Various ATP-dependent chromatin remodeling (ACR) complexes, which play significant roles in protein/DNA and protein/protein interactions in chromatin and regulate transcription, DNA repair processes such as DSB repair (DSBR), nucleotide excision repair (NER), and cross-link repair, also affect BER. ACR complexes utilize the energy of ATP hydrolysis to restructure nucleosomes on chromatin [181][182][183], thereby affecting gene expression profile and DNA repair. Four structurally related, but functionally distinct, ACR complex families were identified: SWI/SNF (switching defective/sucrose nonfermenting; most extensively studied), ISWI (imitation switch), CHD (chromodomain, helicase, DNA binding), and INO80 (inositol requiring 80).…”

“…The Access-Repair-Restore model [182,202] provides an accepted view of DNA repair in chromatin, where chromatin remodeling is essential for the DNA repair machineries to get access to the damaged DNA. For BER, it is still not clear how chromatin remodeling and the associated histone PTMs initiate BER.…”