Article Summary 25/8/23

发表于

Article title

NASP modulates histone turnover to drive PARP inhibitor resistance

NASP and PARP1-involving histone H3/H4 cycle in PARPi resistant cells
NASP and PARP1-involving histone H3/H4 cycle in PARPi resistant cells

Journal

Nature

Tags

PARP1; PARP inhibitor, genetics, drug resistance

Introduction

Homologous recombination-deficient cancer is a prevalent disease including breast cancer and ovarian cancer. To treat such cancers, PARP inhibitors are developed and approved to clinical trial. However, PARP inhibitors exhibit drug resistance. To explore the origin of PARPi drug resistance mass efforts had been made, mainly towards downstream pathways of PARP inhibition such as the function rescue of homologous recombination. However, whether PARPi affects PARP substrate: chromatin, and whether it is relevant to drug resistance is yet unknown.

This work

Here, this work illustrated that PARPi induces the dissociation of H3/H4 from cell chromatin. Next, they found INO80 complex-NASP could protect the dissociated H3/H4 from being degraded by proteosome, thus maintaining genome integrity to generate drug resistance.

In this article, traditional genetic methods, including gene knockdown, combined with gene knockout-FACS screening approaches were used to discover gene involved in PARPi-mediated H3/H4 dissociation.

However, the article does not mention the process of H3/H4 recycling in chromatin mediated by NASP and PARP1. Further investigations need to be performed.

doi

10.1038/s41586-025-09414-z