TY - JOUR
T1 - STK19 facilitates the clearance of lesion-stalled RNAPII during transcription-coupled DNA repair
AU - van den Heuvel, Diana
AU - Rodríguez-Martínez, Marta
AU - van der Meer, Paula J.
AU - Nieto Moreno, Nicolas
AU - Park, Jiyoung
AU - Kim, Hyun-Suk
AU - van Schie, Janne J. M.
AU - Wondergem, Annelotte P.
AU - D'Souza, Areetha
AU - Yakoub, George
AU - Herlihy, Anna E.
AU - Kashyap, Krushanka
AU - Boissière, Thierry
AU - Walker, Jane
AU - Mitter, Richard
AU - Apelt, Katja
AU - de Lint, Klaas
AU - Kirdök, Idil
AU - Ljungman, Mats
AU - Wolthuis, Rob M. F.
AU - Cramer, Patrick
AU - Schärer, Orlando D.
AU - Kokic, Goran
AU - Svejstrup, Jesper Q.
AU - Luijsterburg, Martijn S.
N1 - Publisher Copyright:
© 2024 The Authors
PY - 2024/12/12
Y1 - 2024/12/12
N2 - Transcription-coupled DNA repair (TCR) removes bulky DNA lesions impeding RNA polymerase II (RNAPII) transcription. Recent studies have outlined the stepwise assembly of TCR factors CSB, CSA, UVSSA, and transcription factor IIH (TFIIH) around lesion-stalled RNAPII. However, the mechanism and factors required for the transition to downstream repair steps, including RNAPII removal to provide repair proteins access to the DNA lesion, remain unclear. Here, we identify STK19 as a TCR factor facilitating this transition. Loss of STK19 does not impact initial TCR complex assembly or RNAPII ubiquitylation but delays lesion-stalled RNAPII clearance, thereby interfering with the downstream repair reaction. Cryoelectron microscopy (cryo-EM) and mutational analysis reveal that STK19 associates with the TCR complex, positioning itself between RNAPII, UVSSA, and CSA. The structural insights and molecular modeling suggest that STK19 positions the ATPase subunits of TFIIH onto DNA in front of RNAPII. Together, these findings provide new insights into the factors and mechanisms required for TCR.
AB - Transcription-coupled DNA repair (TCR) removes bulky DNA lesions impeding RNA polymerase II (RNAPII) transcription. Recent studies have outlined the stepwise assembly of TCR factors CSB, CSA, UVSSA, and transcription factor IIH (TFIIH) around lesion-stalled RNAPII. However, the mechanism and factors required for the transition to downstream repair steps, including RNAPII removal to provide repair proteins access to the DNA lesion, remain unclear. Here, we identify STK19 as a TCR factor facilitating this transition. Loss of STK19 does not impact initial TCR complex assembly or RNAPII ubiquitylation but delays lesion-stalled RNAPII clearance, thereby interfering with the downstream repair reaction. Cryoelectron microscopy (cryo-EM) and mutational analysis reveal that STK19 associates with the TCR complex, positioning itself between RNAPII, UVSSA, and CSA. The structural insights and molecular modeling suggest that STK19 positions the ATPase subunits of TFIIH onto DNA in front of RNAPII. Together, these findings provide new insights into the factors and mechanisms required for TCR.
KW - CSA
KW - CSB
KW - DNA repair
KW - ELOF1
KW - RNA polymerase II
KW - STK19
KW - TFIIH
KW - UVSSA
KW - nucleotide excision repair
KW - transcription
UR - http://www.scopus.com/inward/record.url?scp=85210545445&partnerID=8YFLogxK
U2 - 10.1016/j.cell.2024.10.018
DO - 10.1016/j.cell.2024.10.018
M3 - Article
C2 - 39547229
SN - 0092-8674
VL - 187
SP - 7107-7125.e25
JO - Cell
JF - Cell
IS - 25
ER -