RNA∶DNA hybrids initiate quasi-palindrome-associated mutations in highly transcribed yeast DNA.
RNA∶DNA hybrids initiate quasi-palindrome-associated mutations in highly transcribed yeast DNA.
复制标题
DOI：
10.1371/journal.pgen.1003924
复制
发表时间：
2013-11
期刊：
影响因子：
4.5
通讯作者：
Jinks-Robertson S
中科院分区：
文献类型：
--
作者：
Kim N;Cho JE;Li YC;Jinks-Robertson S
RNase H enzymes promote genetic stability by degrading aberrant RNA∶DNA hybrids and by removing ribonucleotide monophosphates (rNMPs) that are present in duplex DNA. Here, we report that loss of RNase H2 in yeast is associated with mutations that extend identity between the arms of imperfect inverted repeats (quasi-palindromes or QPs), a mutation type generally attributed to a template switch during DNA synthesis. QP events were detected using frameshift-reversion assays and were only observed under conditions of high transcription. In striking contrast to transcription-associated short deletions that also are detected by these assays, QP events do not require Top1 activity. QP mutation rates are strongly affected by the direction of DNA replication and, in contrast to their elevation in the absence of RNase H2, are reduced when RNase H1 is additionally eliminated. Finally, transcription-associated QP events are limited by components of the nucleotide excision repair pathway and are promoted by translesion synthesis DNA polymerases. We suggest that QP mutations reflect either a transcription-associated perturbation of Okazaki-fragment processing, or the use of a nascent transcript to resume replication following a transcription-replication conflict. Mutation rates are correlated with the level of gene expression in budding yeast, demonstrating a link between transcription and stability of the underlying DNA template. In the current work, we describe a novel type of transcription-associated mutation that converts imperfect inverted repeats (quasi-palindromes or QPs) to perfect inverted repeats. Using appropriate mutation reporters, we demonstrate that QP mutations are strongly affected by the direction of DNA replication and have distinctive genetic requirements. Most notably, rates of transcription-associated QP events are regulated by the RNase H class of enzymes, which are specialized to process the RNA component of RNA∶DNA hybrids. The source of the RNA∶DNA hybrids that initiate QP mutations is unclear, but could reflect transcripts that remain stably base-paired with the DNA template, or aberrant processing of the RNA primers normally used to initiate DNA synthesis. These studies further expand the diverse ways that transcription affects the mutation landscape, and establish a novel way that RNA∶DNA hybrids can contribute to genetic instability. The high conservation of basic DNA-related metabolic processes suggests that results in yeast will be broadly applicable in higher eukaryotes.
登录
查看更多内容
影响因子：
14.9
作者：
Chon H;Sparks JL;Rychlik M;Nowotny M;Burgers PM;Crouch RJ;Cerritelli SM
通讯作者：
Cerritelli SM
DOI：
10.1073/pnas.0812715106
发表时间：
2009-04-07
影响因子：
11.1
作者：
Lehner, Kevin;Jinks-Robertson, Sue
通讯作者：
Jinks-Robertson, Sue
影响因子：
3.8
作者：
Kim, Nayun;Abdulovic, Amy L.;Jinks-Robertson, Sue
通讯作者：
Jinks-Robertson, Sue
影响因子：
5.3
作者：
Kim, Nayun;Jinks-Robertson, Sue
通讯作者：
Jinks-Robertson, Sue
DOI：
10.1126/science.1191125
发表时间：
2010-07-02
期刊：
Science (New York, N.Y.)
影响因子：
--
作者：
Hicks WM;Kim M;Haber JE
通讯作者：
Haber JE