Genome protection: histone H4 and beyond
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MINI-REVIEW
Genome protection: histone H4 and beyond Kundan Kumar1,2 · Romila Moirangthem1 · Rupinder Kaur1 Received: 29 May 2020 / Revised: 9 June 2020 / Accepted: 9 June 2020 © The Author(s) 2020
Abstract Histone proteins regulate cellular factors’ accessibility to DNA, and histone dosage has previously been linked with DNA damage susceptibility and efficiency of DNA repair pathways. Surplus histones are known to impede the DNA repair process by interfering with the homologous recombination-mediated DNA repair in Saccharomyces cerevisiae. Here, we discuss the recent finding of association of methyl methanesulfonate (MMS) resistance with the reduced histone H4 gene dosage in the pathogenic yeast Candida glabrata. We have earlier shown that while the low histone H3 gene dosage led to MMS susceptibility, the lack of two H4-encoding ORFs, CgHHF1 and CgHHF2, led to resistance to MMS-induced DNA damage. This resistance was linked with a higher rate of homologous recombination (HR). Taking these findings further, we review the interactome analysis of histones H3 and H4 in C. glabrata. We also report that the arginine residue present at the 95th position in the C-terminal tail of histone H4 protein is required for complementation of the MMS resistance in the Cghhf1Δhhf2Δ mutant, thereby pointing out a probable role of this residue in association with HR factors. Additionally, we present evidence that reduction in H4 protein levels may constitute an important part of varied stress responses in C. glabrata. Altogether, we present an overview of histone H4 dosage, HR-mediated repair of damaged DNA and stress resistance in this opportunistic human fungal pathogen. Keywords Human fungal pathogens · Genome integrity · Homologous recombination · Methyl methanesulfonate (MMS) · Stress resistance · Histones · Chromatin
Introduction Maintenance of genome integrity is pivotal to sustain life, with genome encountering regular threats from endogenous and exogenous stressors (Friedberg 2003; Ciccia and Elledge 2010). Genome stability is affected by various events including changes in the nucleotide sequence of DNA, single- and double-strand breaks in DNA, replication fork stalling and DNA–protein crosslinks (Lindahl Communicated by M. Kupiec. Kundan Kumar and Romila Moirangthem contributed equally to this work. * Rupinder Kaur [email protected] 1
Laboratory of Fungal Pathogenesis, Centre for DNA Fingerprinting and Diagnostics (CDFD), Hyderabad, Telangana 500039, India
Graduate Studies, Manipal Academy of Higher Education, Manipal, Karnataka 576104, India
2
1993; Tretyakova et al. 2015). These alterations in DNA are sensed, signaled, and subsequently repaired by a large repertoire of proteins whose subcellular localization, activity and functions are exquisitely coordinated (Friedberg 2003; Ciccia and Elledge 2010). It is, therefore, not surprising that the genome integrity is closely entwined with regulation of the cell cycle progression (Novák et al. 2018). However, an unaltered genome is a double-edged sword. While on
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