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Mullin-Bernstein, Z.

Publications and source records attributed to Mullin-Bernstein, Z..

2 recordsLinked to original sources

Midzone bundles of the mammalian anaphase spindle are mechanically coupled both locally and globally

Robust chromosome segregation requires the anaphase spindle to both preserve and remodel its structure under force. How it does so remains unclear as probing mechanics during anaphases short lifetime is challenging. Here, we use microneedles to pull on mammalian anaphase midzone bundles and ask how they respond to and transmit force across space and time. We find that midzone bundles locally transmit force to each other in the spindles short axis over multiple timescales. Along the spindles long axis, midzone bundles globally transmit force: rather than bundles sliding apart or detaching under force, the spindle shortens. This reveals strong anchorage and resistance to outward sliding, and that spindle elongation requires all midzone bundles to elongate. This global force transmission is stronger for short-lived forces and is strictly PRC1-dependent, indicating limited mechanistic redundancy. In sum, the anaphase spindle acts as a single mechanical unit over short timescales to resist and transmit force, while remodeling over long timescales to segregate chromosomes. SummaryUsing microneedle manipulation, Mullin-Bernstein et al. show that microtubule bundles of the mammalian anaphase spindle are mechanically coupled, transmitting force both laterally and between spindle poles. These strong connections may help ensure coordinated and error-free chromosome segregation.

cell biology↗

Discovery of a first-in-class inhibitor of the PRMT5-substrate adaptor interaction

PRMT5 and its substrate adaptor proteins (SAPs), pICln and Riok1, are synthetic lethal dependencies in MTAP-deleted cancer cells. SAPs share a conserved PRMT5 binding motif (PBM) which mediates binding to a surface of PRMT5 distal to the catalytic site. This interaction is required for methylation of several PRMT5 substrates, including histone and spliceosome complexes. We screened for small molecule inhibitors of the PRMT5-PBM interaction and validated a compound series which binds to the PRMT5-PBM interface and directly inhibits binding of SAPs. Mode of action and structure determination studies revealed that these compounds form a covalent bond between a halogenated pyridazinone group and cysteine 278 of PRMT5. Optimization of the starting hit produced a lead compound, BRD0639, which engages the target in cells, disrupts the PRMT5-RIOK1 complex, and reduces substrate methylation. BRD0639 is a first-in-class PBM-competitive small molecule that can support studies of PBM-dependent PRMT5 activities and the development of novel PRMT5 inhibitors that selectively target these functions.

cancer biology↗