title: Hydrogen peroxide induced genomic instability in nucleotide excision repair-deficient lymphoblastoid cells.
abstract: BACKGROUND
  The Nucleotide Excision Repair (NER) pathway specialises in UV-induced DNA damage repair. Inherited defects in the NER can predispose individuals to Xeroderma Pigmentosum (XP). UV-induced DNA damage cannot account for the manifestation of XP in organ systems not directly exposed to sunlight. While the NER has recently been implicated in the repair of oxidative DNA lesions, it is not well characterised. Therefore we sought to investigate the role of NER factors Xeroderma Pigmentosum A (XPA), XPB and XPD in oxidative DNA damage-repair by subjecting lymphoblastoid cells from patients suffering from XP-A, XP-D and XP-B with Cockayne Syndrome to hydrogen peroxide (H2O2).
  
  
  RESULTS
  Loss of functional XPB or XPD but not XPA led to enhanced sensitivity towards H2O2-induced cell death. XP-deficient lymphoblastoid cells exhibited increased susceptibility to H2O2-induced DNA damage with XPD showing the highest susceptibility and lowest repair capacity. Furthermore, XPB- and XPD-deficient lymphoblastoid cells displayed enhanced DNA damage at the telomeres. XPA- and XPB-deficient lymphoblastoid cells also showed differential regulation of XPD following H2O2 treatment.
  
  
  CONCLUSIONS
  Taken together, our data implicate a role for the NER in H2O2-induced oxidative stress management and further corroborates that oxidative stress is a significant contributing factor in XP symptoms. Resistance of XPA-deficient lymphoblastoid cells to H2O2-induced cell death while harbouring DNA damage poses a potential cancer risk factor for XPA patients. Our data implicate XPB and XPD in the protection against oxidative stress-induced DNA damage and telomere shortening, and thus premature senescence.
authors.affiliation: Department of Physiology, Yong Loo Lin School of Medicine, National University of Singapore, 117597, Singapore.
authors.forename: Kalpana
authors.initials: K
authors.lastname: Gopalakrishnan
authors.affiliation: Department of Physiology, Yong Loo Lin School of Medicine, National University of Singapore, 117597, Singapore.
authors.forename: Grace Kah Mun
authors.initials: GKM
authors.lastname: Low
authors.affiliation: Department of Physiology, Yong Loo Lin School of Medicine, National University of Singapore, 117597, Singapore.
authors.forename: Aloysius Poh Leong
authors.initials: APL
authors.lastname: Ting
authors.affiliation: Department of Physiology, Yong Loo Lin School of Medicine, National University of Singapore, 117597, Singapore.
authors.forename: Prarthana
authors.initials: P
authors.lastname: Srikanth
authors.affiliation: Division of Biosciences, School of Health Sciences and Social Care, Brunel University, Uxbridge UB8 3PH, UK.
authors.forename: Predrag
authors.initials: P
authors.lastname: Slijepcevic
authors.affiliation: Department of Physiology, Yong Loo Lin School of Medicine, National University of Singapore, 117597, Singapore.
authors.forename: M Prakash
authors.initials: MP
authors.lastname: Hande