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Review
. 2016 Jun 1;17(6):856.
doi: 10.3390/ijms17060856.

DNA Damage and Repair in Schizophrenia and Autism: Implications for Cancer Comorbidity and Beyond

Enni Markkanen  1 , Urs Meyer  2 , Grigory L Dianov  3   4
Affiliations
Review

DNA Damage and Repair in Schizophrenia and Autism: Implications for Cancer Comorbidity and Beyond

Enni Markkanen et al. Int J Mol Sci. .

Abstract

Schizophrenia and autism spectrum disorder (ASD) are multi-factorial and multi-symptomatic psychiatric disorders, each affecting 0.5%-1% of the population worldwide. Both are characterized by impairments in cognitive functions, emotions and behaviour, and they undermine basic human processes of perception and judgment. Despite decades of extensive research, the aetiologies of schizophrenia and ASD are still poorly understood and remain a significant challenge to clinicians and scientists alike. Adding to this unsatisfactory situation, patients with schizophrenia or ASD often develop a variety of peripheral and systemic disturbances, one prominent example of which is cancer, which shows a direct (but sometimes inverse) comorbidity in people affected with schizophrenia and ASD. Cancer is a disease characterized by uncontrolled proliferation of cells, the molecular origin of which derives from mutations of a cell's DNA sequence. To counteract such mutations and repair damaged DNA, cells are equipped with intricate DNA repair pathways. Oxidative stress, oxidative DNA damage, and deficient repair of oxidative DNA lesions repair have been proposed to contribute to the development of schizophrenia and ASD. In this article, we summarize the current evidence of cancer comorbidity in these brain disorders and discuss the putative roles of oxidative stress, DNA damage and DNA repair in the aetiopathology of schizophrenia and ASD.

Keywords: DNA base excision repair; XRCC1; autism; cancer; neurodevelopmental disorders; oxidative DNA damage; oxidative stress; schizophrenia.

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Figures

Figure 1
Figure 1
Simplified scheme of base excision repair (BER). Modified after [76,78]. (A) BER is initiated by damage-specific DNA glycosylases, which identify and release the corrupted base by hydrolysis of the N-glycosylic bond linking the DNA base to the sugar phosphate backbone (reviewed in [76,79]). The arising abasic (AP) site is further processed by AP-endonuclease 1 (APE1), and depending on the mechanism by which the DNA base was removed, end processing of the modified 3′- and 5′-termini is performed by a variety of end-processing enzymes. This processing results in the generation of a 3′-OH and a 5′-P group adjacent to the DNA gap or break; (B) Single-strand breaks (SSBs) can also arise from direct disintegration of oxidised deoxyribose. This process usually leads to damaged or modified termini, which are processed by a variety of enzymes to 3′-OH and 5′-P groups. SSBs are then handled identically to the BER intermediates from this point onward; (C) Further processing of the SSB containing intermediate stemming from either source is carried out by the core BER complex that includes DNA polymerase β (Pol β), XRCC1 (X-ray repair cross-complementation group 1) and DNA ligase IIIa (Lig III). Pol β possesses a dRP-lyase activity that removes the 5′-sugar phosphate and also, functioning as a DNA polymerase, adds one nucleotide to the 3′-end of the arising single-nucleotide gap. Finally, the XRCC1-Lig III complex seals the DNA ends, therefore accomplishing complete DNA repair [71,80,81,82].
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