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

A Correction to this article was published on 29 September 2020

This article has been updated

Abstract

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.

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Fig. 1

Change history

  • 29 September 2020

    The original version of this article unfortunately requires correction where the name of a methyltransferase was represented wrongly.

Abbreviations

53BP1:

p53 binding protein

Aβ:

Amyloid-beta

AD:

Alzheimer’s disease

ADMA/Rme2a:

Asymmetric dimethylarginine

AID:

Activation-Induced cytidine deaminase

ALS:

Amyotrophic lateral sclerosis

AOA1:

Ataxia-ocular motor Apraxia 1

APTX:

Aprataxin

ATLD:

Ataxia-telangiectasia like disease

ATM:

Ataxia telangiectasia mutated

ATR:

Ataxia telangiectasia mutated and Rad3 related

BER:

Base excision repair

BRCA1:

Breast cancer susceptibility protein 1

BS:

Bloom syndrome

CS:

Cockayne syndrome

DDR:

DNA damage response

DSB:

Double strand breaks

ETFβ:

Electron transfer flavoprotein

FOXO1:

Forkhead transcription factors of class O

FRDA:

Friedreich ataxia

FTD:

Frontotemporal dementia

FUS/TLS:

Fused in sarcoma/Translocated in liposarcoma

FXS:

Fragile X syndrome

FXTAS:

Fragile X-associated Tremor/Ataxia syndrome

GAR/RGG:

Glycine-and-arginine-rich

GG-NER:

Global genomic nucleotide excision repair

HD:

Huntington’s disease

HP1:

Heterochromatin protein 1

HR:

Homologous recombination

JMJC:

Jumonji domain-containing

MCSZ:

Microcephaly with seizures

MMA/Rme1:

Monomethylated arginine

MMR:

Mismatch repair

MRE11:

Meiotic recombination 11

mtDNA:

Mitochondrial DNA

NBS:

Nijmegen breakage syndrome

NER:

Nucleotide excision repair

NFT:

Neurofibrillary tangles

NHEJ:

Non-homologous end joining

PAD:

Protein arginine deiminases

PD:

Parkinson’s disease

PKMT:

Protein lysine methyltransferases

PNKP:

Polynucleotide Kinase/Phosphatase

PRMT:

Protein arginine Methyltransferases

PTMs:

Post translational modifications

ROS:

Reactive oxygen species

RTS:

Rothmund–Thomson syndrome

SCAN1:

Spinocerebellar ataxia with axonal neuropathy

SDMA/Rme2s:

Symmetric dimethylarginine 4

SSB:

Single strand breaks

TC-NER:

Transcription coupled nucleotide excision repair

TDP1:

Tyrosyl DNA-phosphodiesterase 1

TDP-43:

TAR DNA binding protein-43

TOP1:

Topoisomerase 1

TOP1cc:

TOP1 cleavage complex

TTD:

Trichothiodystrophy

UBAP2L:

Ubiquitin-associated protein 2-like

VHL:

von Hippel-Lindau

XP:

Xeroderma pigmentosum

WS:

Werner syndrome

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Acknowledgments

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

Funding

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

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

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Correspondence to Madhusoodanan Urulangodi or Abhishek Mohanty.

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Urulangodi, M., Mohanty, A. DNA damage response and repair pathway modulation by non-histone protein methylation: implications in neurodegeneration. J. Cell Commun. Signal. 14, 31–45 (2020). https://doi.org/10.1007/s12079-019-00538-2

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Keywords

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