Emerging links between premature ageing and defective DNA repair

Hanawalt, Philip C.

doi:10.1016/j.mad.2008.03.007

Cited by 15 publications

(15 citation statements)

References 28 publications

(23 reference statements)

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“…Arrested Pol II by DNA lesion is proposed as the initial signal for the recruitment of repair proteins involved in TCR though the detailed recruiting mechanism remains to be elucidated (Malik et al, 2010; Sarker et al, 2005; Troelstra et al, 1993; Troelstra et al, 1992; van den Boom et al, 2004; van Gool et al, 1997). Defects in genes involved in TCR cause premature aging and human diseases, such as Cockayne Syndrome, Xeroderma Pigmentosum, Trichothiodystrophy, UV-sensitive syndrome, and Cerebro-Oculo-Facio-Skeletal Syndrome (Hanawalt, 2008; Hanawalt and Spivak, 2008; Jaakkola et al, 2010; Laugel et al, 2010). Finally, persistently arrested Pol II undergoes ubiquitylation and subsequent degradation (Lindsey-Boltz and Sancar, 2007; Svejstrup, 2007; Wilson, Harreman, and Svejstrup, 2013).…”

Section: Introductionmentioning

confidence: 99%

RNA polymerase II transcriptional fidelity control and its functional interplay with DNA modifications

Wang

Chong

et al. 2015

Critical Reviews in Biochemistry and Molecular Biology

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Accurate genetic information transfer is essential for life. As a key enzyme involved in the first step of gene expression, RNA polymerase II (Pol II) must maintain high transcriptional fidelity while it reads along DNA template and synthesizes RNA transcript in a stepwise manner during transcription elongation. DNA lesions or modifications may lead to significant changes in transcriptional fidelity or transcription elongation dynamics. In this review, we will summarize recent progress towards understanding the molecular basis of RNA Pol II transcriptional fidelity control and impacts of DNA lesions and modifications on Pol II transcription elongation.

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Section: Introductionmentioning

confidence: 99%

RNA polymerase II transcriptional fidelity control and its functional interplay with DNA modifications

Wang

Chong

et al. 2015

Critical Reviews in Biochemistry and Molecular Biology

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“…Finally, as the last resort to remove persistently arrested Pol II, the arrested Pol II undergoes ubiquitylation and degradation (7, 14, 29). Defects in genes involved in TCR cause premature aging and several human diseases, such as UV-sensitive syndrome, Cockayne Syndrome, Xeroderma Pigmentosum, Trichothiodystrophy, and Cerebro-Oculo-Facio-Skeletal Syndrome (13, 30–35). Several excellent reviews on transcription-coupled DNA damage processing can be found elsewhere (13–17).…”

Section: Introductionmentioning

confidence: 99%

Molecular basis of transcriptional fidelity and DNA lesion-induced transcriptional mutagenesis

Plouffe

et al. 2014

DNA Repair

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Maintaining high transcriptional fidelity is essential for life. Some DNA lesions lead to significant changes in transcriptional fidelity. In this review, we will summarize recent progress towards understanding the molecular basis of RNA polymerase II (Pol II) transcriptional fidelity and DNA lesion-induced transcriptional mutagenesis. In particular, we will focus on the three key checkpoint steps of controlling Pol II transcriptional fidelity: insertion (specific nucleotide selection and incorporation), extension (differentiation of RNA transcript extension of a matched over mismatched 3'-RNA terminus), and proofreading (preferential removal of misincorporated nucleotides from the 3'-RNA end). We will also discuss some novel insights into the molecular basis and chemical perspectives of controlling Pol II transcriptional fidelity through structural, computational, and chemical biology approaches.

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“…A distinct feature of neurons is that unlike the glial cells, they are terminally differentiated, postmitotic in which replication-associated DNA repair cannot occur [4]. However, recent studies have indicated that high levels of DNA damage in neurons could activate their S phase entry that either promotes DNA repair or more commonly apoptosis [71].…”

Section: Ber/ssbr In Central Nervous System (Cns)mentioning

confidence: 99%

“…Imbalance in genome damage and its repair has been proposed as a major reason for accumulation of unrepaired genome damage in neurodegenerative diseases, although the bases for such an imbalance were not understood until recently [4, 13, 105, 106]. Defective neuronal DNA repair resulting in genomic instability has been linked to neuronal dysfunctions.…”

Section: Ber/ssbr Defects In Neurodegenerative Diseasesmentioning

confidence: 99%

“…High level of ROS-induced genome damage occurs in cells (e.g., neurons in brain) with high respiration rate. Furthermore, the long life span of postmitotic, differentiated neurons and lack of replication-coupled repair compared to cycling cells promote accumulation of unrepaired DNA damage over time [4]. It is thus not surprising that persistent oxidative genome damage has been implicated in several neurodegenerative diseases including AD [5, 6], PD [5, 7, 8] and Huntington’s disease (HD; [9, 10]) and amyotrophic lateral sclerosis (ALS; [11, 12]).…”

Section: Introductionmentioning

confidence: 99%

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Oxidative Genome Damage and its Repair in Neurodegenerative Diseases: Function of Transition Metals as a Double-Edged Sword

Hegde

Rao

et al. 2011

JAD

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The neurons in the central nervous system (CNS) with high O2 consumption and prolonged life span are chronically exposed to high levels of reactive oxygen species (ROS). Accumulation of ROS-induced genome damage in the form of oxidized bases and single-strand breaks (SSBs) as well as their defective or reduced repair in the brain has been implicated in the etiology of various neurological disorders including Alzheimer’s/Parkinson’s diseases (AD/PD). Although inactivating mutations in some DNA repair genes have been linked to hereditary neurodegenerative diseases, the underlying mechanisms of repair deficiencies for the sporadic diseases is not understood. The ROS-induced DNA damages are predominantly repaired via highly conserved and regulated base excision/SSB repair (BER/SSBR) pathway. We recently made an interesting discovery that transition metals iron (Fe) and copper (Cu) which accumulate excessively in the brains of AD, PD and other neurodegenerative diseases, act as a ‘double-edged sword’ by inducing genotoxic ROS and inhibiting DNA damage repair at the same time. These metals inhibit the base excision activity of NEIL family DNA glycosylases by oxidizing them, changing their structure, and inhibiting their binding to downstream repair proteins. Metal chelators and reducing agents partially reverse the inhibition, while curcumin with both chelating and reducing activities reverses the inhibition nearly completely. In this review, we have discussed the possible etiological linkage of BER/SSBR defects to neurodegenerative diseases and therapeutic potential of metal chelators in restoring DNA repair capacity.

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Emerging links between premature ageing and defective DNA repair

Cited by 15 publications

References 28 publications

RNA polymerase II transcriptional fidelity control and its functional interplay with DNA modifications

RNA polymerase II transcriptional fidelity control and its functional interplay with DNA modifications

Molecular basis of transcriptional fidelity and DNA lesion-induced transcriptional mutagenesis

Oxidative Genome Damage and its Repair in Neurodegenerative Diseases: Function of Transition Metals as a Double-Edged Sword

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