Judith Haarhuis

Associate staff scientist

My interest lies in the molecular mechanism behind chromosomal architecture. DNA is structured via chromosomal loops created by SMC complexes. I studied how DNA loop extrusion by cohesin is regulated and what the effect of these loops is on cellular behaviour.

These days I focus on another SMC complex, called the SMC5/6 complex. SMC5/6 is involved in genomic maintenance, as it functions in DNA replication and DNA damage repair. Recently, it has been discovered that this complex can similarly to cohesin form DNA loops. Interestingly, the implications of these DNA loops, and the real mechanistic function whereby SMC5/6 acts, remain a mystery.

Molecular Biology

Genetics

Cell Biology

Nature Communications, 2022

Keeping heterochromatin in check

The genome consists of regions of transcriptionally active euchromatin and more silent heterochromatin. In a fantastic collaboration with the lab of Elzo de Wit, we reveal that the formation of heterochromatin domains requires cohesin turnover on DNA. We suggest that the Mediator-CDK module contributes to gene expression by limiting the formation of dense heterochromatin domains.

Check out JUDITH'S COOL PAPER!

Nature Structural & Molecular Biology, 2022

A brake for the looping cycle

The acetylation of cohesin’s SMC3 subunit is a dynamic process that involves the acetyltransferase ESCO1 and deacetylase HDAC8. We show that this cohesin acetylation cycle controls the 3D genome by converting cohesin into a PDS5-bound state. We suggest that PDS5 acts as a brake that enables the pausing and restart of loop enlargement. The cohesin acetylation cycle hereby provides punctuation in the process of genome folding.

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Nature, 2020

Genome folding by cohesin & CTCF

Cohesin folds the genome into loops that are anchored by CTCF. In a great collaboration with the lab of Daniel Panne, we show that the interaction of the CTCF N-terminus with the SA2-SCC1 subunits of cohesin stabilises cohesin at CTCF sites. This interaction is essential for CTCF-anchored loops genome-wide. We propose that CTCF enables chromatin loop formation by protecting cohesin against loop release.

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Cell, 2017

Loop enlargement by cohesin

The cohesin complex shapes the 3D genome by looping together regulatory elements along chromosomes. We find that chromatin loop size can be increased, and that the duration with which cohesin embraces DNA determines the degree to which loops are enlarged. We conclude that the balanced activity of SCC2/NIPBL-dependent loop extension, and WAPL-mediated DNA release, allows cohesin to correctly structure chromosomes.

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Molecular Cell, 2016

How does cohesin release DNA?

Cohesin complexes by default undergo a continuous cycle of DNA entrapment and release. We uncover a functional asymmetry within the heart of cohesin's ABC-like ATPase machinery. Both ATPase sites contribute to DNA loading, whereas DNA release is controlled specifically by one site. We propose that Smc3 acetylation locks cohesin rings around sister DNAs by counteracting an activity associated with this release ATPase site.

Read THIS PAPER, its COMMENTARY, and view OUR COVER.

Developmental Cell, 2014

The logic of X-shaped chromosomes

The X shape of chromosomes is one of the iconic images in biology. Cohesin in fact connects the sisters along their entire length until early mitosis. Then, cohesin's antagonist Wapl allows the separation of chromosome arms, resulting in the X shape of mitotic chromosomes. Check out our review on cohesin, its regulation, and the logic of X-shaped chromosomes.

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Current Biology, 2013

Why chromosomes are X-shaped

The classical X-shape of human chromosomes is the consequence of two distinct waves of cohesin removal. First cohesin is removed from arms, and only then from centromeres. We find that this two-step removal process allows the disentanglement of sister chromatids, and the correction of erroneous microtubule-kinetochore attachments. The two-step cohesin removal process thus is essential for proper chromosome segregation.

Read THIS PAPER and its COMMENTARY.

Workexperience

2004-2008. – Bachelor of Science, University of Utrecht.
2008-2010 – Master of Science, University of Utrecht including an intership in the lab of Karlene Cimprich at Stanford University.
2010 – 2016 – PhD in Molecular Biology, Utrecht University, in the lab of Benjamin Rowland at The Netherlands Cancer Institute.

Judith Haarhuis

Associate staff scientist

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