Genetic instability associated with loop or stem-loop structures within transcription units can be independent of nucleotide excision repair

John A. Burns, Moinuddin A. Chowdhury, Laura Cartularo, Christian Berens, David Scicchitano

Research output: Contribution to journalArticle

Abstract

Simple sequence repeats (SSRs) are found throughout the genome, and under some conditions can change in length over time. Germline and somatic expansions of trinucleotide repeats are associated with a series of severely disabling illnesses, including Huntington's disease. The underlying mechanisms that effect SSR expansions and contractions have been experimentally elusive, but models suggesting a role for DNA repair have been proposed, in particular the involvement of transcription-coupled nucleotide excision repair (TCNER) that removes transcription-blocking DNA damage from the transcribed strand of actively expressed genes. If the formation of secondary DNA structures that are associated with SSRs were to block RNA polymerase progression, TCNER could be activated, resulting in the removal of the aberrant structure and a concomitant change in the region's length. To test this, TCNER activity in primary human fibroblasts was assessed on defined DNA substrates containing extrahelical DNA loops that lack discernible internal base pairs or DNA stem-loops that contain base pairs within the stem. The results show that both structures impede transcription elongation, but there is no corresponding evidence that nucleotide excision repair (NER) or TCNER operates to remove them.

Original languageEnglish (US)
Pages (from-to)3498-3516
Number of pages19
JournalNucleic acids research
Volume46
Issue number7
DOIs
StatePublished - Apr 20 2018

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DNA Repair
Microsatellite Repeats
DNA
Base Pairing
Trinucleotide Repeat Expansion
Huntington Disease
DNA-Directed RNA Polymerases
DNA Damage
Fibroblasts
Genome
Genes

ASJC Scopus subject areas

  • Genetics

Cite this

Genetic instability associated with loop or stem-loop structures within transcription units can be independent of nucleotide excision repair. / Burns, John A.; Chowdhury, Moinuddin A.; Cartularo, Laura; Berens, Christian; Scicchitano, David.

In: Nucleic acids research, Vol. 46, No. 7, 20.04.2018, p. 3498-3516.

Research output: Contribution to journalArticle

Burns, John A. ; Chowdhury, Moinuddin A. ; Cartularo, Laura ; Berens, Christian ; Scicchitano, David. / Genetic instability associated with loop or stem-loop structures within transcription units can be independent of nucleotide excision repair. In: Nucleic acids research. 2018 ; Vol. 46, No. 7. pp. 3498-3516.
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