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Cellular and Molecular Life Sciences

, Volume 67, Issue 21, pp 3573–3587 | Cite as

Functions of disordered regions in mammalian early base excision repair proteins

  • Muralidhar L. Hegde
  • Tapas K. Hazra
  • Sankar MitraEmail author
Multi-Author Review

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.

Keywords

Base excision repair DNA glycosylases End processing proteins Disordered terminal segments Single strand breaks Reactive oxygen species Repair complex Protein–protein and protein–DNA interactions 

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

Notes

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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Copyright information

© Springer Basel AG 2010

Authors and Affiliations

  • Muralidhar L. Hegde
    • 1
  • Tapas K. Hazra
    • 1
    • 2
  • Sankar Mitra
    • 1
    Email author
  1. 1.Department of Biochemistry and Molecular BiologyUniversity of Texas Medical BranchGalvestonUSA
  2. 2.Department of Internal MedicineUniversity of Texas Medical BranchGalvestonUSA

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