From chromatin architectural protein to histone chaperone

Poly [ADP-ribose] polymerase 1 (PARP-1) is a highly abundant in cells. At a nuclear concentration of about one PARP-1molecule per 20 nucleosomes, it has the potential to affect many nuclear processes. It catalyzes the NAD+-dependent polymerization of long chains of poly-ADP ribose (PAR) onto itself in response to DNA damage and other cues. Here, we report that Auto modification of PARP-1 may play a role in both chromatin structure protein and histone chaperone.

We determined dissociation constants of the various PARP-1–chromatin complexes using high-throughput interactions by fluorescence intensity FRET. Unmodified PARP-1 engages in at least two high-affinity binding modes with chromatin, one of which does not involve free DNA ends, consistent with its role as a chromatin architectural protein.

Auto-PARylation of Parp-1activated by a variety of stimuli associated with transcription and DNA repair regulates its ability to compact chromatin. This modification reduces PARP-1 affinity for intact chromatin but not for nucleosomes with exposed DNA ends. AM–PARP-1 directly competes with DNA for histones, as predicted from our affinity measurements and as observed for other histone chaperones.

We offer a model of PARP-1 binds nucleosomes with high affinity throughout the genome, thereby condensing chromatin.

ALS and spastic paraplegia (SP) are classified by degeneration of motor neurons, leading to muscle atrophy and even premature death. One kind of MNDs is associated with impaired mitochondrial respiration and mitochondrial distribution. Here, we show that Miro1 is essential for development of cranial motor nuclei.

Mitochondrial Rho (Miro) GTPase proteins are critical for transport because they are the only known surface receptors that attach mitochondria to these adaptors and motors. The movement of neuronal mitochondria between the cell body and the synapse is regulated by adaptors called trafficking kinesin proteins. We construct a cre-loxP system to knock out Miro1 in mice.

Unluckily, the KO mice are lethality. The germ-line Miro1 KO mouse completes embryogenesis but fails to breathe and dies at birth. These data indicate that death of Miro1 KO mice is caused by specific defects in motor neurons required for breathing after birth.

Next, we explore the molecular mechanism. We found that Miro1 deletion leads to loss of specific neurons required for respiration. Mitochondria labeled with Mito Tracker had the characteristic tubular morphology and were distributed throughout the cytoplasm and in filopodia, the Miro1 KO MEFs were clustered around the nucleus and absent from filopodia.

To summary, these findings show that primary defects in mitochondrial motility and distribution and cause neurological disease.