ATR checkpoint kinase and CRLl super( beta TRCP) collaborate to degrade ASFla and thus repress genes overlapping with clusters of stalled replication forks

• Published in: Genes & development 2014-04, Vol.28 (8), p.875-887
• Main Authors: Im, Jun-Sub, Keaton, Mignon, Lee, Kyung Yong, Kumar, Pankaj, Park, Jonghoon, Dutta, Anindya
• Format: Article
• Language: English
• ISSN: 0890-9369; 1549-5477
• DOI: 10.1101/gad.239194.114

Many agents used for chemotherapy, such as doxorubicin, interfere with DNA replication, but the effect of this interference on transcription is largely unknown. Here we show that doxorubicin induces the firing of dense clusters of neoreplication origins that lead to clusters of stalled replication forks in gene-rich parts of the genome, particularly on expressed genes. Genes that overlap with these clusters of stalled forks are actively dechromatinized, unwound, and repressed by an ATR-dependent checkpoint pathway. The ATR checkpoint pathway causes a histone chaperone normally associated with the replication fork, ASFla, to degrade through a CRLl super( beta TRCP)-dependent ubiquitination/proteasome pathway, leading to the localized dechromatinization and gene repression. Therefore, a globally active checkpoint pathway interacts with local clusters of stalled forks to specifically repress genes in the vicinity of the stalled forks, providing a new mechanism of action of chemotherapy drugs like doxorubicin. Finally, ASFla-depleted cancer cells are more sensitive to doxorubicin, suggesting that the 7%-10% of prostate adenocarcinomas and adenoid cystic carcinomas reported to have homozygous deletion or significant underexpression of ASFla should be tested for high sensitivity to doxorubicin.