Inhibition of nucleotide excision repair by high mobility group protein HMGA1

Jennifer E Adair; Youngho Kwon; Gregory A Dement; Michael J Smerdon; Raymond Reeves

doi:10.1074/jbc.M505600200

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Inhibition of nucleotide excision repair by high mobility group protein HMGA1

Journal article

Open access

Peer reviewed

Inhibition of nucleotide excision repair by high mobility group protein HMGA1

Jennifer E Adair, Youngho Kwon, Gregory A Dement, Michael J Smerdon and Raymond Reeves

The Journal of biological chemistry, Vol.280(37), pp.32184-32192

09/16/2005

DOI: https://doi.org/10.1074/jbc.M505600200

Handle:

https://hdl.handle.net/2376/115735

PMID: 16033759

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https://doi.org/10.1074/jbc.M505600200View

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Abstract

Xenopus

Blotting, Southern

Oligonucleotides - chemistry

Up-Regulation

Humans

Gene Expression Regulation, Neoplastic

Base Pair Mismatch

RNA, Messenger - metabolism

Receptors, Interleukin - metabolism

Cell Nucleus - metabolism

Flow Cytometry

Transfection

Ultraviolet Rays

RNA Interference

Time Factors

HMGA1a Protein - physiology

Sensitivity and Specificity

Pyrimidine Dimers - chemistry

HMGA1a Protein - chemistry

Transgenes

Circular Dichroism

Dimerization

Promoter Regions, Genetic

Interleukin-2 Receptor alpha Subunit

Magnetic Resonance Spectroscopy

Cell Separation

Cell Survival

Oocytes - metabolism

Gene Expression Regulation

DNA - chemistry

Animals

DNA Repair

Cell Line, Tumor

Mutation

Genome

Dose-Response Relationship, Radiation

The mammalian non-histone "high mobility group" A (HMGA) proteins are the primary nuclear proteins that bind to the minor groove of AT-rich DNA. They may, therefore, influence the formation and/or repair of DNA lesions that occur in AT-rich DNA, such as cyclobutane pyrimidine dimers (CPDs) induced by UV radiation. Employing both stably transfected lines of human MCF7 cells containing tetracycline-regulated HMGA1 transgenes and primary Hs578T tumor cells, which naturally overexpress HMGA1 proteins, we have shown that cells overexpressing HMGA1a protein exhibit increased UV sensitivity. Moreover, we demonstrated that knockdown of intracellular HMGA1 concentrations via two independent methods abrogated this sensitivity. Most significantly, we observed that HMGA1a overexpression inhibited global genomic nucleotide excision repair of UV-induced CPD lesions in MCF-7 cells. Consistent with these findings in intact cells, DNA repair experiments employing Xenopus oocyte nuclear extracts and lesion-containing DNA substrates demonstrated that binding of HMGA1a markedly inhibits removal of CPDs in vitro. Furthermore, UV "photo-foot-printing" demonstrated that CPD formation within a long run of Ts (T(18)-tract) in a DNA substrate changes significantly when HMGA1 is bound prior to UV irradiation. Together, these results suggest that HMGA1 directly influences both the formation and repair of UV-induced DNA lesions in intact cells. These findings have important implications for the role that HMGA protein overexpression might play in the accumulation of mutations and genomic instabilities associated with many types of human cancers.

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Details

Title: Inhibition of nucleotide excision repair by high mobility group protein HMGA1
Creators: Jennifer E Adair - School of Molecular Biosciences, Biochemistry, and Biophysics, Washingston State University, Pullman, 99164-4660, USA
Youngho Kwon
Gregory A Dement
Michael J Smerdon
Raymond Reeves
Publication Details: The Journal of biological chemistry, Vol.280(37), pp.32184-32192
Academic Unit: Molecular Biosciences, School of
Publisher: United States
Grant note: T-32 GM008336 / NIGMS NIH HHS GM46352 / NIGMS NIH HHS GM71760 / NIGMS NIH HHS ES02614 / NIEHS NIH HHS
Identifiers: 99900548099701842
Language: English
Resource Type: Journal article