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Going GA GA for CLAMP

How one protein produces two results...

What causes a protein to function one way for one chromosome, but differently for another? Perhaps the recently discovered protein CLAMP, will help explain.

Brown University scientists had previously (2013) identified CLAMP (chromatin-linked adaptor for MSL proteins), as the first link between Drosophila's male-specific lethal (MSL) dosage ability to increase transcript levels on the single male X chromosome to equal transcript levels to XX females and achieve genetic parity between the two. As published in Genes and Development.

Now, they have identified a new role for CLAMP as coordinator of how chromosomes are tightly wound to fit within each cell of a developing embryo. The work is also published in Genes and Development.
"It's really exciting because now we have these two separate chromosomes on which CLAMP does vital work. That sets up a compare and contrast strategy where we can see how one protein can function differently in context-specific ways."

Erica Larschan PhD, Department of Molecular Biology, Cellular Biology, and Biochemistry, Brown University, Providence, Rhode Island, USA.

Confirmation of a second life-giving role for CLAMP provides a perfect example of a protein being essential in two completely different ways. In the new work, Brown scientists found long GA repeats bound by CLAMP on chromosome 2L at the "histone locus" of fruit fly cells. This cluster produces proteins that wind DNA tightly so it will fit inside each cell's nucleus.

Approximately 3 feet of DNA is present in each fruit fly cell, so it is essential it be tightly wrapped and condensed. Collaborations between scientists at Brown, University of North Carolina, and Massachusetts General Hospital found CLAMP initiates genes to produce histones and in experiments where scientists interfered with CLAMP, almost universally the fly eggs failed to hatch.
CLAMP binds to DNA all over a fly's genome, but only kicks into action when it finds a long series of repeats of the nucleotides GA.

GA repeats

Abstract – The CLAMP protein links the MSL complex to the X chromosome during Drosophila dosage compensation
The Drosophila male-specific lethal (MSL) dosage compensation complex increases transcript levels on the single male X chromosome to equal the transcript levels in XX females. However, it is not known how the MSL complex is linked to its DNA recognition elements, the critical first step in dosage compensation. Here, we demonstrate that a previously uncharacterized zinc finger protein, CLAMP (chromatin-linked adaptor for MSL proteins), functions as the first link between the MSL complex and the X chromosome. CLAMP directly binds to the MSL complex DNA recognition elements and is required for the recruitment of the MSL complex. The discovery of CLAMP identifies a key factor required for the chromosome-specific targeting of dosage compensation, providing new insights into how subnuclear domains of coordinate gene regulation are formed within metazoan genomes.

Abstract – Histone locus regulation by the Drosophila dosage compensation adaptor protein CLAMP
The conserved histone locus body (HLB) assembles prior to zygotic gene activation early during development and concentrates factors into a nuclear domain of coordinated histone gene regulation. Although HLBs form specifically at replication-dependent histone loci, the cis and trans factors that target HLB components to histone genes remained unknown. Here we report that conserved GA repeat cis elements within the bidirectional histone3–histone4 promoter direct HLB formation in Drosophila. In addition, the CLAMP (chromatin-linked adaptor for male-specific lethal [MSL] proteins) zinc finger protein binds these GA repeat motifs, increases chromatin accessibility, enhances histone gene transcription, and promotes HLB formation. We demonstrated previously that CLAMP also promotes the formation of another domain of coordinated gene regulation: the dosage-compensated male X chromosome. Therefore, CLAMP binding to GA repeat motifs promotes the formation of two distinct domains of coordinated gene activation located at different places in the genome.

All authors: Leila E. Rieder1,13, Kaitlin P. Koreski2,13, Kara A. Boltz3,4,9, Guray Kuzu5,10, Jennifer A. Urban1, Sarah K. Bowman5,11, Anna Zeidman1,12, William T. Jordan III1, Michael Y. Tolstorukov5, William F. Marzluff2,3,4,6,7, Robert J. Duronio2,3,4,7,8 and Erica N. Larschan

Keywords: nuclear bodies histone locus body CLAMP GA repeats GAGA factor dosage compensation

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Aug 31, 2017   Fetal Timeline   Maternal Timeline   News   News Archive

CLAMP protein is responsible for coordinating how DNA in newly replicating embryo cells become properly wound up and structured within a cell. Image credit: Brown University

Phospholid by Wikipedia