DNA damage response and repair pathway modulation by non-histone protein methylation: implications in neurodegeneration

  • Madhusoodanan UrulangodiEmail author
  • Abhishek MohantyEmail author


Protein post-translational modifications (PTMs) have emerged to be combinatorial, essential mechanisms used by eukaryotic cells to regulate local chromatin structure, diversify and extend their protein functions and dynamically coordinate complex intracellular signalling processes. Most common types of PTMs include enzymatic addition of small chemical groups resulting in phosphorylation, glycosylation, poly(ADP-ribosyl)ation, nitrosylation, methylation, acetylation or covalent attachment of complete proteins such as ubiquitin and SUMO. Protein arginine methyltransferases (PRMTs) and protein lysine methyltransferases (PKMTs) enzymes catalyse the methylation of arginine and lysine residues in target proteins, respectively. Rapid progress in quantitative proteomic analysis and functional assays have not only documented the methylation of histone proteins post-translationally but also identified their occurrence in non-histone proteins which dynamically regulate a plethora of cellular functions including DNA damage response and repair. Emerging advances have now revealed the role of both histone and non-histone methylations in the regulating the DNA damage response (DDR) proteins, thereby modulating the DNA repair pathways both in proliferating and post-mitotic neuronal cells. Defects in many cellular DNA repair processes have been found primarily manifested in neuronal tissues. Moreover, fine tuning of the dynamicity of methylation of non-histone proteins as well as the perturbations in this dynamic methylation processes have recently been implicated in neuronal genomic stability maintenance. Considering the impact of methylation on chromatin associated pathways, in this review we attempt to link the evidences in non-histone protein methylation and DDR with neurodegenerative research.


DNA damage response DNA repair Non-histone protein methylation Lysine methylation Arginine methylation Neurodegenerative diseases 



p53 binding protein



Alzheimer’s disease


Asymmetric dimethylarginine


Activation-Induced cytidine deaminase


Amyotrophic lateral sclerosis


Ataxia-ocular motor Apraxia 1




Ataxia-telangiectasia like disease


Ataxia telangiectasia mutated


Ataxia telangiectasia mutated and Rad3 related


Base excision repair


Breast cancer susceptibility protein 1


Bloom syndrome


Cockayne syndrome


DNA damage response


Double strand breaks


Electron transfer flavoprotein


Forkhead transcription factors of class O


Friedreich ataxia


Frontotemporal dementia


Fused in sarcoma/Translocated in liposarcoma


Fragile X syndrome


Fragile X-associated Tremor/Ataxia syndrome




Global genomic nucleotide excision repair


Huntington’s disease


Heterochromatin protein 1


Homologous recombination


Jumonji domain-containing


Microcephaly with seizures


Monomethylated arginine


Mismatch repair


Meiotic recombination 11


Mitochondrial DNA


Nijmegen breakage syndrome


Nucleotide excision repair


Neurofibrillary tangles


Non-homologous end joining


Protein arginine deiminases


Parkinson’s disease


Protein lysine methyltransferases


Polynucleotide Kinase/Phosphatase


Protein arginine Methyltransferases


Post translational modifications


Reactive oxygen species


Rothmund–Thomson syndrome


Spinocerebellar ataxia with axonal neuropathy


Symmetric dimethylarginine 4


Single strand breaks


Transcription coupled nucleotide excision repair


Tyrosyl DNA-phosphodiesterase 1


TAR DNA binding protein-43


Topoisomerase 1


TOP1 cleavage complex




Ubiquitin-associated protein 2-like


von Hippel-Lindau


Xeroderma pigmentosum


Werner syndrome



MU thank Prof. Asha Kishore, Dr. Srinivas G, and Dr. Cibin TR, SCTIMST, for their constant encouragement, stimulating discussion, suggestions and support throughout.

Author contributions

MU and AM equally contributed in conceptualization, writing, and editing the manuscript.

Funding information

MU acknowledge the “seed fund” (#6113) from the Sree Chitra Tirunal Institute for Medical Sciences and Technology (SCTIMST).

Compliance with ethical standards

Conflict of interest

The authors declare no conflict of interest.


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© The International CCN Society 2019

Authors and Affiliations

  1. 1.Department of BiochemistrySree Chitra Tirunal Institute for Medical Sciences and TechnologyThiruvananthapuramIndia
  2. 2.Rajiv Gandhi Cancer Institute and Research CentreNew DelhiIndia

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