Abstract
In mammals the bulky DNA adduct lesions known to result in deleterious phenotypes are acted upon and removed from the genomic DNA by nucleotide excision repair (NER) pathway. TFIIH multi-protein complex with its important helicase–Xeroderma Pigmentosum Protein (XPD) serves as the pivotal factor for opening up of the damaged lesion DNA site and carry out the repair process. The initial damage verification step of the TFIIH is in part dependent upon the helicase activity of XPD. Besides, XPD is also actively involved in the initiation steps of transcription and in the regulation of the cell cycle and apoptosis. In this review, we will be exploring the new insights in scientific research on the functioning of the NER pathway, the role of TFIIH as the central complex of NER, the pivotal helicase XPD as the lynchpin of NER and the effects of various single nucleotide polymorphisms (SNPs) of XPD on its functioning and their consequent role in colorectal carcinogenesis.
Highlights
Colorectal carcinogenesis is a multifactorial and multigene process that is controlled by various gatekeeper and caretaker genes via definite pathway, referred to as the adenoma–carcinoma sequence/model (Vogelstein et al, 1988)
The genes implicated in colorectal tumorigenesis that are silenced by hypermethylation include DNA repair genes such as methylguanine methyltransferase (MGMT) and MLH1, tumor suppressors (p16, APC, insulin-like growth factor 2, and HIC1), cell cycle regulatory genes (Mutated In Colorectal Cancers/MCC) and Wnt signaling antagonists known as SFRPs
The differential role play by both proteins has been shown to toggle between transcription functions and nucleotide excision repair (NER) functions (Oksenych and Coin, 2010); wherein XPB ATPase activity is essentially required for DNA opening in both NER and transcription but its helicase activity is dedicated to only promoter escape in transcription process
Summary
Colorectal carcinogenesis is a multifactorial and multigene process that is controlled by various gatekeeper and caretaker genes via definite pathway, referred to as the adenoma–carcinoma sequence/model (Vogelstein et al, 1988). CpG island methylator phenotype (CIMP), referred to as methylator phenotype of CRC tumorigenesis involves gene silencing or transcriptional inactivation by CpG island methylation in tumor suppressor gene promoters. It plays a major role in about 35% of CRCs (Sporadic as well as Hereditary) (Cunningham et al, 2010; Sameer and Nissar, 2016). The genes implicated in colorectal tumorigenesis that are silenced by hypermethylation include DNA repair genes such as methylguanine methyltransferase (MGMT) and MLH1, tumor suppressors (p16, APC, insulin-like growth factor 2, and HIC1), cell cycle regulatory genes (Mutated In Colorectal Cancers/MCC) and Wnt signaling antagonists known as SFRPs (secreted frizzled-related proteins). MMR repairs the small loops within the duplex DNA that arise from nucleotide misincorporations—either by base—base mismatches or by insertion/deletion loops (Sameer et al, 2014)
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