Biology subjects

Henen, M. A.

Publications and source records attributed to Henen, M. A..

3 recordsLinked to original sources

bioRxiv2023

SASH1 interacts with TNKS2 and promotes human melanocyte stem cell maintenance

Both aging spots (hyperpigmentation) and hair graying (lack of pigmentation) are associated with aging, two seemingly opposite pigmentation phenotypes. It is not clear how they are mechanistically connected. This study investigated the underlying mechanism in a family with an inherited pigmentation disorder. Clinical examinations identified accelerated hair graying and skin dyspigmentation (intermixed hyper and hypopigmentation) in the family members carrying the SASH1S519N variant. Cell assays indicated that SASH1 promoted stem-like characteristics in human melanocytes, and SASH1S519N was defective in this function. Multiple assays showed that SASH1 binds to tankyrase 2 (TNKS2), which is required for SASH1s promotion of stem-like function. Further, the SASH1S519N variant is in a bona fide Tankyrase-binding motif, and SASH1S519N alters the binding kinetics and affinity. Results here indicate SASH1 as a novel protein regulating the appropriate balance between melanocyte stem cells (McSC) and mature melanocytes (MCs), with S519N variant causing defects. We propose that dysfunction of McSC maintenance connects multiple aging-associated pigmentation phenotypes in the general population.

cell biology↗

bioRxiv2023

An evolutionarily conserved strategy for ribosome binding and inhibition by β-coronavirus non-structural protein 1

An important pathogenicity factor of SARS-CoV-2 and related coronaviruses is Nsp1, which suppresses host gene expression and stunts antiviral signaling. SARS-CoV-2 Nsp1 binds the ribosome to inhibit translation through mRNA displacement and induces degradation of host mRNAs through an unknown mechanism. Here we show that Nsp1-dependent host shutoff is conserved in diverse coronaviruses, but only Nsp1 from {beta}-CoV inhibits translation through ribosome binding. The C-terminal domain of all {beta}-CoV Nsp1s confers high-affinity ribosome-binding despite low sequence conservation. Modeling of interactions of four Nsp1s to the ribosome identified few absolutely conserved amino acids that, together with an overall conservation in surface charge, form the {beta}-CoV Nsp1 ribosome-binding domain. Contrary to previous models, the Nsp1 ribosome-binding domain is an inefficient translation inhibitor. Instead, the Nsp1-CTD likely functions by recruiting Nsp1s N-terminal "effector" domain. Finally, we show that a viral cis-acting RNA element has co-evolved to fine-tune SARS-CoV-2 Nsp1 function, but does not provide similar protection against Nsp1 from related viruses. Together, our work provides new insight into the diversity and conservation of ribosome-dependent host-shutoff functions of Nsp1, knowledge that could aide future efforts in pharmacological targeting of Nsp1 from SARS-CoV-2, but also related human-pathogenic {beta}-coronaviruses. Our study also exemplifies how comparing highly divergent Nsp1 variants can help to dissect the different modalities of this multi-functional viral protein.

biochemistry↗

bioRxiv2022

PBRM1 BD2 and BD4 associate with RNA to facilitate chromatin association

PBRM1 is a subunit of the PBAF chromatin remodeling complex, which is mutated in 40-50% of clear cell renal cell carcinoma patients. It is thought to largely function as a chromatin binding subunit of the PBAF complex, but the molecular mechanism underlying this activity is not fully known. PBRM1 contains six tandem bromodomains which are known to cooperate in binding of nucleosomes acetylated at histone H3 lysine 14 (H3K14ac). Here we demonstrate that the second and fourth bromodomains from PBRM1 also bind nucleic acids, selectively associating with double stranded RNA elements. Disruption of the RNA binding pocket is found to compromise PBRM1 chromatin binding and inhibit PBRM1-mediated cellular growth effects.

biochemistry↗