ZBTB48 causes persistent chromatin bridges in ALT-positive cells
Prof. Dennis KAPPEI
Cancer Science Institute of Singapore (CSI)
Assistant Professor, Department of Biochemistry, Yong Loo Lin School of Medicine
National University of Singapore (NUS)
invited by Maria Teresa Teixeira
Monday 9 September 2024, at 10:30 am at Conference room – IBPC (third floor)
Telomere maintenance is a universal hallmark of cancers to sustain the unlimited proliferative potential. In ~85% of cancers, telomere shortening is mitigated by reactivated telomerase expression while the other ~15% use a recombination-based mechanism, termed Alternative Lengthening of Telomeres (ALT). ALT-positive tumors are particularly prevalent in glioma and sarcoma, affecting 25-75% of cases, and are characterized by aberrant chromatin due to loss of epigenetic remodellers such as ATRX and DAXX.
We and others had previously established that the zinc finger protein ZBTB48/TZAP directly binds to telomeric DNA and acts as a negative regulator of telomere length in both telomerase-positive and ALT-positive cancer cells. In the latter, ZBTB48 is particularly abundant at telomeres and its overexpression had been reported to cause rapid telomere shortening, but the exact molecular mechanism has not been definitively established. Here, we describe that ZBTB48 overexpression induces chromatin bridge formation as the primary cause of telomere attrition upstream of telomere-driven genomic instability. ZBTB48-induced chromatin bridge formation is exclusive to ALT-positive cellular contexts and leads to concomitant hyperactivation of the ALT pathway. Mechanistically, these phenotypes are based on ZBTB48-dependent recruitment of chromatin remodellers as identified by proximity labelling coupled to label-free quantitative mass spectrometry. Overall, our data demonstrate a profound role of ZBTB48 on telomere stability unique to ALT-positive contexts.