Nuclear-enriched protein phosphatase 4 ensures outer kinetochore assembly prior to nuclear dissolution

Abstract

A landmark event in the transition from interphase to mitosis in metazoans is nuclear envelope breakdown (NEBD). Important mitotic events occur prior to NEBD, including condensation of replicated chromosomes and assembly of kinetochores to rapidly engage spindle microtubules. Here, we show that nuclear-enriched protein phosphatase 4 (PP4) ensures robust assembly of the microtubule-coupling outer kinetochore prior to NEBD. In the absence of PP4, chromosomes exhibit extended monopolar orientation after NEBD and subsequently mis-segregate. A secondary consequence of diminished outer kinetochore assembly is defective sister chromatid resolution. After NEBD, a cytoplasmic activity compensates for PP4 loss, leading to outer kinetochore assembly and recovery of chromosomes from monopolar orientation to significant bi-orientation. The Ndc80-Ska microtubule-binding module of the outer kinetochore is required for this recovery. PP4 associates with the inner kinetochore protein CENP-C; however, disrupting the PP4–CENP-C interaction does not perturb chromosome segregation. These results establish that PP4-dependent outer kinetochore assembly prior to NEBD is critical for timely and proper engagement of chromosomes with spindle microtubules.

Protein Phosphatase 4 Is Required for Centrobin Function in DNA Damage Repair

“…Understanding the molecular etiology of cancer plays an indispensable role in shaping the future of cancer diagnosis and personalized therapy for patients. The Ser/Thr protein phosphatase 4, PP4, has been extensively studied and found to play a critical role in several cellular processes, including cell cycle regulation [ 15 , 24 , 30 , 31 , 54 , 55 , 56 , 57 , 58 , 59 , 60 ] and DNA repair [ 16 , 17 , 19 , 61 , 62 , 63 , 64 ]. The impact of PP4 on cancer development has been investigated, revealing that alterations in PP4 expression, subcellular localization, or activity can contribute to tumorigenesis.…”

Protein phosphatase 4 is required for Centrobin function in DNA damage repair

“…Understanding the molecular etiology of cancer plays an indispensable role in shaping the future of cancer diagnosis and personalized therapy for patients. The Ser/Thr protein phosphatase 4, PP4, has been extensively studied and found to play a critical role in several cellular processes, including cell cycle regulation [15,24,30,31,[54][55][56][57][58][59][60] and DNA repair [16,17,19,[61][62][63][64]. The impact of PP4 on cancer development has been investigated, revealing that alterations in PP4 expression, subcellular localization, or activity can contribute to tumorigenesis.…”

A PP4 foszfatáz és a Centrobin kapcsolata a DNS hibajavítás késői szakaszaiban

“…Szerepe van a centroszóma érésben és a mikrotubulusok nukleációjában (31). A fehérje hiányában csökken a centroszómális α-Tubulin és Aurora A fehérjék szintje, valamint PP4c gátlásakor a Plk1 (Polo-like kinase 1) mennyisége is csökken (128,129). Ezt alátámasztja, hogy a PP4c deléciója Drosophila melanogaster embriókban, úgynevezett cmm (centrosomes minus microtubules) szemiletális fenotípust okoz.…”