[Nov. 22] 117th IRCMS Seminar

October 4 2024

We would like to inform you that the 117th IRCMS seminar has been scheduled as below.
* This IRCMS seminar is open to everyone.

Date      : November 22, 2024 (Friday)

Time      : 16:00-17:00

ZOOM　: Meeting ID: 926 9076 4050
            　 Passcode: Sem22Nov

Speaker : Dr. Makoto T. Hayashi (Kyoto University)

Title        : The Mechanism of Mitotic Arrest-Dependent Telomere Deprotection

Abstract 

Telomeres, composed of repetitive DNA and the shelterin complex (including TRF1/TRF2), protect chromosome ends from activating the DNA damage response (DDR). TRF2 aids the formation of a T-loop by enabling the 3' telomere end to invade double-stranded telomeric DNA. Disruption of telomere function, through either telomere shortening or loss of shelterin function, leads to telomere deprotection. This activates DDR, causing cell cycle arrest, chromosome fusions, and/or cell death, which underlie replicative senescence or tumorigenesis depending on the cellular context. We discovered that during mitotic arrest, Aurora Kinase B (AURKB) causes mitotic arrest-dependent (MAD) telomere deprotection, the only known active telomere deprotection mechanism (paper 1). We proposed this is involved in the pharmacological effects of anti-tumor mitotic inhibitors and preventing cells from transformation during telomere crisis (paper 2). However, the molecular mechanism of MAD telomere deprotection remained elusive.

Using interactomics, super-resolution imaging, and molecular biology techniques, we identified the Chromosome Passenger Complex (CPC) and the BLM-TOP3A-RMI1/2 (BTR) complex as key players in this process. AURKB phosphorylates TRF2 and TRF1: the phosphorylation of TRF2 basic domain attenuates its protective function on T-loop against BTR activity, while TRF1 phosphorylation paradoxically promotes deprotection through interaction with the CPC complex (paper 3). In this seminar, I will discuss our recent findings on MAD telomere deprotection and its potential role in normal cell cycle.

2-3 major papers:

1. A Telomere Dependent DNA Damage Checkpoint Induced by Prolonged Mitotic Arrest
    Makoto T. Hayashi, Anthony J. Cesare, James A. J. Fitzpatrick, Eros Lazzerini-Denchi, Jan Karlseder*
    Nature Structural & Molecular Biology, 2012, Mar 11; 19(4): 387-394

2. Cell Death During Crisis Is Mediated by Mitotic Telomere Deprotection
    Makoto T. Hayashi, Anthony J. Cesare, Teresa Rivera, Jan Karlseder*
    Nature, 2015, June 25; 522: 492-496

3. A CPC-shelterin-BTR axis regulates mitotic telomere deprotection
    Diana Romero-Zamora*, Samuel Rogers*, Ronnie Ren Jie Low, Andrew B. Robinson, Scott G. Page,
    Blake J. E. Lane, Noa Lamm, Fuyuki Ishikawa, Makoto T. Hayashi**, Anthony J. Cesare**
    bioRxiv, 2024, Jan 10, *Co-first; **Co-correspondence

Flyer: (Click to enlarge)