TY - JOUR
T1 - Control of transcriptional pausing by biased thermal fluctuations on repetitive genomic sequences
AU - Imashimizu, Masahiko
AU - Afek, Ariel
AU - Takahashi, Hiroki
AU - Lubkowska, Lucyna
AU - Lukatsky, David B.
N1 - Funding Information:
We thank Mikhail Kashlev and Yoshikazu Nakamura for supporting our research and for helpful discussions, Nobuo Shimamoto and Donald L. Court for critical reading of the manuscript and for insightful comments, and Taku Oshima for helpful discussions regarding the PWM analysis. M.I. is also grateful to Nobuo Shimamoto for discussions regarding chemical kinetics. This work was supported by the Intramural Research Program of the NIH/National Cancer Institute (to Mikhail Kashlev), by MEXT KAKENHI Grants 16K18671 and 16H06279 (to H.T.), and by Japan Society for the Promotion of Science KAKENHI Grant 16H06692 (to M.I.). A.A. is supported by an Integrated DNA Technologies postdoctoral fellowship.
PY - 2016/11/22
Y1 - 2016/11/22
N2 - In the process of transcription elongation, RNA polymerase (RNAP) pauses at highly nonrandom positions across genomic DNA, broadly regulating transcription; however, molecular mechanisms responsible for the recognition of such pausing positions remain poorly understood. Here, using a combination of statistical mechanical modeling and high-throughput sequencing and biochemical data, we evaluate the effect of thermal fluctuations on the regulation of RNAP pausing. We demonstrate that diffusive backtracking of RNAP, which is biased by repetitive DNA sequence elements, causes transcriptional pausing. This effect stems from the increased microscopic heterogeneity of an elongation complex, and thus is entropydominated. This report shows a linkage between repetitive sequence elements encoded in the genome and regulation of RNAP pausing driven by thermal fluctuations.
AB - In the process of transcription elongation, RNA polymerase (RNAP) pauses at highly nonrandom positions across genomic DNA, broadly regulating transcription; however, molecular mechanisms responsible for the recognition of such pausing positions remain poorly understood. Here, using a combination of statistical mechanical modeling and high-throughput sequencing and biochemical data, we evaluate the effect of thermal fluctuations on the regulation of RNAP pausing. We demonstrate that diffusive backtracking of RNAP, which is biased by repetitive DNA sequence elements, causes transcriptional pausing. This effect stems from the increased microscopic heterogeneity of an elongation complex, and thus is entropydominated. This report shows a linkage between repetitive sequence elements encoded in the genome and regulation of RNAP pausing driven by thermal fluctuations.
KW - Backtracking
KW - Nonconsensus protein-DNA binding
KW - RNA polymerase
KW - Repetitive DNA sequence elements
KW - Thermal fluctuations
UR - http://www.scopus.com/inward/record.url?scp=84996490291&partnerID=8YFLogxK
U2 - 10.1073/pnas.1607760113
DO - 10.1073/pnas.1607760113
M3 - Article
C2 - 27830653
AN - SCOPUS:84996490291
SN - 0027-8424
VL - 113
SP - E7409-E7417
JO - Proceedings of the National Academy of Sciences of the United States of America
JF - Proceedings of the National Academy of Sciences of the United States of America
IS - 47
ER -