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Publication

Ubiquitination-Deficient Mutations in Human Piwi Cause Male Infertility by Impairing Histone-to-Protamine Exchange during Spermiogenesis.

Cell | 2017

Genetic studies have elucidated critical roles of Piwi proteins in germline development in animals, but whether Piwi is an actual disease gene in human infertility remains unknown. We report germline mutations in human Piwi (Hiwi) in patients with azoospermia that prevent its ubiquitination and degradation. By modeling such mutations in Piwi (Miwi) knockin mice, we demonstrate that the genetic defects are directly responsible for male infertility. Mechanistically, we show that MIWI binds the histone ubiquitin ligase RNF8 in a Piwi-interacting RNA (piRNA)-independent manner, and MIWI stabilization sequesters RNF8 in the cytoplasm of late spermatids. The resulting aberrant sperm show histone retention, abnormal morphology, and severely compromised activity, which can be functionally rescued via blocking RNF8-MIWI interaction in spermatids with an RNF8-N peptide. Collectively, our findings identify Piwi as a factor in human infertility and reveal its role in regulating the histone-to-protamine exchange during spermiogenesis.

Pubmed ID: 28552346 RIS Download

Research resources used in this publication

Additional research tools detected in this publication

New England Biolabs (RRID:SCR_013517)

Antibodies used in this publication

Associated grants

Agency: NIGMS NIH HHS, United States
Id: R01 GM049369
Agency: NIGMS NIH HHS, United States
Id: R01 GM052872
Agency: NHGRI NIH HHS, United States
Id: R01 HG004659

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This is a list of tools and resources that we have found mentioned in this publication.

New England Biolabs (tool)

RRID:SCR_013517

An Antibody supplier

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Anti-Ubiquitin Antibody (P4D1) (antibody)

RRID:AB_628423

This monoclonal targets Ubiquitin

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Monoclonal ANTI-FLAG® M2 antibody (antibody)

RRID:AB_259529

This monoclonal targets FLAG

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Protamine 2 (C-14) (antibody)

RRID:AB_2284440

This polyclonal targets Protamine 2 (C-14)

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Protamine 1 (A-17) (antibody)

RRID:AB_2171310

This polyclonal targets PRM1

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HIWI (N-17) (antibody)

RRID:AB_2165430

This polyclonal targets PIWIL1

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Rabbit Anti-Tubulin alpha Polyclonal Antibody, Unconjugated (antibody)

RRID:AB_1664134

This polyclonal targets Tubulin alpha

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TNP1 antibody (antibody)

RRID:AB_2206757

This polyclonal targets TNP1

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H3K27me3-human (antibody)

RRID:AB_2616029

This unknown targets H3K27me3

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Ubiquityl-Histone H2B (Lys120) (D11) XP Rabbit mAb (antibody)

RRID:AB_10693452

This monoclonal targets Ubiquityl-Histone H2B (Lys120) (D11) XP Rabbit mAb

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Anti-Histone H3 Antibody, Unconjugated (antibody)

RRID:AB_331563

This polyclonal targets Histone H3

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Mouse Anti-Actin, beta Monoclonal Antibody, Horseradish Peroxidase Conjugated, Clone AC-15 (antibody)

RRID:AB_262011

This monoclonal targets Actin, beta

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ImageJ (software resource)

RRID:SCR_003070

Open source Java based image processing software program designed for scientific multidimensional images. ImageJ has been transformed to ImageJ2 application to improve data engine to be sufficient to analyze modern datasets.

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