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Review
. 2008 Jul-Aug;129(7-8):408-15.
doi: 10.1016/j.mad.2008.04.010. Epub 2008 May 1.

Tissue-specific accelerated aging in nucleotide excision repair deficiency

Laura J Niedernhofer  1
Affiliations
Review

Tissue-specific accelerated aging in nucleotide excision repair deficiency

Laura J Niedernhofer. Mech Ageing Dev. 2008 Jul-Aug.

Abstract

Nucleotide excision repair (NER) is a multi-step DNA repair mechanism that removes helix-distorting modified nucleotides from the genome. NER is divided into two subpathways depending on the location of DNA damage in the genome and how it is first detected. Global genome NER identifies and repairs DNA lesions throughout the genome. This subpathway of NER primarily protects against the accumulation of mutations in the genome. Transcription-coupled (TC)-NER rapidly repairs lesions in the transcribed strand of DNA that block transcription by RNA polymerase II. TC-NER prevents cell death in response to stalled transcription. Defects in NER cause three distinct human diseases: xeroderma pigmentosum, Cockayne syndrome and trichothiodystrophy. Each of these syndromes is characterized by premature onset of pathologies that overlap with those associated with old age in humans. This reveals the contribution of DNA damage to multiple age-related diseases. Tissues affected include the skin, eye, bone marrow, nervous system and endocrine axis. This review emphasizes accelerated aging associated with xeroderma pigmentosum and discusses the cause of these pathologies, either mutation accumulation or cell death as a consequence of failure to repair DNA damage.

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Figures

Figure 1
Figure 1. Schematic diagram of nucleotide excision repair
Helix-distorting DNA lesions, for example UV-induced cyclopyrimidine dimes T∩T) are recognized throughout the genome by the protein complex XPC-HR23B. Lesion recognition is facilitated by the DDB complex (DDB1 and XPE/DDB2) specifically in the case of DNA damage caused by UV radiation. DDB is part of the Cul4A complex, which ubiquitylates XPC, leading to its stable association with damaged DNA. This subpathway of NER is called global genome NER (GG-NER). Lesions on the transcribed strand of DNA, which block RNA polymerase II-mediated transcription, activate transcription-coupled NER (TC-NER). TC-NER is facilitated by CSB, CSA and XAB2. Either XPC in GG-NER or CSB and CSA in TC-NER recruit the transcription factor TFIIH to the site of damage. XPG stabilizes TFIIH. The XPB and XPD subunits of TFIIH are helicases that unwind the DNA around the lesion. XPA and RPA then bind and stabilize this unwound intermediate and recruit XPF-ERCC1. This endonuclease incises the damaged strand of DNA 5’ to the lesion, while XPG makes the 3’ incision. The lesion is removed in a single-stranded oligonucleotide, leaving behind a gap, which is filled by the replication machinery comprised of polymerase δ and ε, PCNA, RPA and RFC. The DNA backbone is sealed by DNA Ligase I or DNA Ligase 3-XRCC1.
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