Anthracyclines are highly effective chemotherapeutic agents that cause DNA and chromatin damage. One member of the anthracyclines, aclarubicin, has recently gained therapeutic interest due to its ability to kill cancer cells through chromatin-based mechanisms, thus avoiding the off-target effects associated with DNA damage. Despite this, the molecular mechanism of action leading to aclarubicin-induced chromatin damage remains elusive. Here we performed Cleavage Under Targets and Tagmentation (CUT&Tag) of RNA polymerase II (Pol II) and other transcriptional regulators in human cells during aclarubicin treatment. We found that aclarubicin strongly disrupts the replication-coupled histone genes, resulting in a nonproductive accumulation of Pol II-transcription machinery here beyond the levels at other genes. We attribute this sensitivity to the dense Pol II loading and rapid transcription of the histone genes, which intensify the chromatin-disrupting effects of aclarubicin at these loci. Together, our findings support the effectiveness of aclarubicin as an anticancer drug and point to the histone gene cluster as a promising target for therapeutic intervention.
These findings establish SPRTN as an rDNA-associated repair factor that couples genotoxic damage resolution to Pol I transcriptional resilience, defining the SPRTN-Pol I axis as a determinant of nucleolar homeostasis and therapeutic vulnerability in lung adenocarcinoma.
Mansi Sharma, Srikanth Karnati, S. Ergün et al.· Frontiers in Oncology· 0 citations
Global upregulation of transcription, or hypertranscription, is observed in most human cancers, driven by the action of oncogene-encoded transcription factors (TFs). TF interactions with RNA Polymerase II (Pol II) are mediated by kinases that phosphorylate the Pol II C-terminal domain (CTD) to drive productive elonga...
S. Henikoff, Robert N. Eisenman, K. Ahmad· Epigenetics & Chromatin· 0 citations
Anthracyclines, like doxorubicin, are cornerstone therapies against pediatric sarcomas, and are a first-line treatment for virtually all osteosarcoma patients. While doxorubicin is classified as a topoisomerase II inhibitor whose antineoplastic activity is historically attributed to DNA damage, osteosarcomas are noto...
Poly(ADP-ribose) polymerase inhibitors (PARPi) exploit synthetic lethality to treat BRCA1/2-mutated ovarian cancer, yet clinical responses are often incomplete and resistance frequently emerges. PARPi exert cytotoxic effects by inhibiting single-strand break repair and trapping PARP on DNA, which impedes replication fo...
Na Li, Kousalya Lavudi, Qian-Yun Ge et al.· Cancer Research· 0 citations
It is shown that the non-homologous end joining (NHEJ) enzyme Artemis is a key player in the process and a major target for treatment of human B-cell acute lymphoblastic leukemia (ALL), and genetic loss of Artemis ablates this synergy underscoring its critical role in this drug interaction.
Melissa L. Folkerts, C. Hom, Angie Nguyen et al.· Communications Biology· 0 citations
Findings reveal a previously unrecognized function of TBK1 in modulating the DNA-damage response, linking inflammatory signaling to genome destabilization and identifying the TBK1-MRE11 axis as a potential target to enhance chemotherapeutic efficacy are revealed.
Wei Zhou, Xiangyu Wang, Susanne S. Steigleder et al.· Proceedings of the National...· 0 citations
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