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Functions of disordered regions in mammalian early base excision repair proteins

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Abstract

Reactive oxygen species, generated endogenously and induced as a toxic response, produce several dozen oxidized or modified bases and/or single-strand breaks in mammalian and other genomes. These lesions are predominantly repaired via the conserved base excision repair (BER) pathway. BER is initiated with excision of oxidized or modified bases by DNA glycosylases leading to formation of abasic (AP) site or strand break at the lesion site. Structural analysis by experimental and modeling approaches shows the presence of a disordered segment commonly localized at the N- or C-terminus as a characteristic signature of mammalian DNA glycosylases which is absent in their bacterial prototypes. Recent studies on unstructured regions in DNA metabolizing proteins have indicated their essential role in interaction with other proteins and target DNA recognition. In this review, we have discussed the unique presence of disordered segments in human DNA glycosylases, and AP endonuclease involved in the processing of glycosylase products, and their critical role in regulating repair functions. These disordered segments also include sites for posttranslational modifications and nuclear localization signal. The teleological basis for their structural flexibility is discussed.

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Abbreviations

BER:

Base excision repair

SSBR:

Single-strand break repair

AP:

Abasic

APE:

AP endonuclease

ROS:

Reactive oxygen species

RNS:

Reactive nitrogen species

SSB:

Single-strand break

PONDR:

Prediction of naturally disordered regions in proteins

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Acknowledgments

The research in the authors’ laboratory is supported by USPHS grants, R01 CA81063, R01 CA53791, P01 CA92586 and P30 ES06676 (S.M.) and R01 CA 102271, R21 ES017353 (T.K.H). Because of the limited focus of the article on protein disorder in early BER proteins, many appropriate references could not be included, for which the authors apologize. We thank Mitra lab members for various stimulating discussions during preparation of this review.

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Hegde, M.L., Hazra, T.K. & Mitra, S. Functions of disordered regions in mammalian early base excision repair proteins. Cell. Mol. Life Sci. 67, 3573–3587 (2010). https://doi.org/10.1007/s00018-010-0485-5

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